4,4-Difluoro-1,2,3,4-tetrahydro-5h-1-benzazepine derivatives or salts thereof

ABSTRACT

4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivatives, which have excellent arginine vasopressin V 2  activity and are useful for a drug for the treatment of central diabetes insipidus and/or nocturia.

TECHNICAL FIELD OF THE INVENTION

The present invention relates to a novel4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative or a saltthereof, which is useful as a medicament, especially as a drug for thetreatment of central diabetes insipidus or nocturia, and to a medicamentcomprising the compound as an active ingredient.

BACKGROUND ART

Arginine vasopressin (AVP) is a peptide consisting of 9 amino acids,which is biosynthesized and secreted from the hypothalamus/pituitarygland. AVP receptors are classified into three subtypes, i.e. V_(1a),V_(1b), and V₂. It is known that the main pharmaceutical effects of AVPin peripheral are vasoconstriction through the V_(1a) receptor, andantidiuresis through the V₂ receptor. As a medicament for selectivelystimulating V₂ receptors, desmopressin has been synthesized (by deletingthe amino acid of cystein in position 1 of AVP, and converting arginineof position 8 into a d form) and is used in the treatment of centraldiabetes insipidus (Journal of Japanese Academy of Endocrinology, 54,676-691, 1978). However, an oral agent of desmopressin has very lowbiological availability and requires a high dose. Thus, desmopressinformulation is expensive, and side effect based on variation ofabsorption according to individuals is often recognized. Therefore,there is a demand for the development of a nonpeptide antidiureticagent, which selectively stimulates V₂ receptors and has high biologicalavailability.

In addition, according to diversified medical treatment and agingpopulation, it has become rare to employ a single medicine, and in mostcases, plural kinds of medicines are administrated simultaneously or atintervals. The same applies to the field of medicament for stimulatingAVP. A medicine is inactivated by the action of a medicine metabolismenzyme in the liver and is converted into a metabolite, and among theseenzymes, cytochrome P450 (CYP) is most important. Several types ofmolecular species of CYP exist, but if plural kinds of medicines thatare metabolized by the same molecular species of CYP compete on themetabolism enzyme, it is believed that metabolism is somewhat inhibited,although the extent of the inhibition varies depending on affinity ofeach of the medicines for CYP. As a result, interactions betweenmedicines such as blood concentration increase or blood half lifeprolongation, etc. are expressed.

Such interactions between medicines are not desirable, except in a casewhere synergism is intended, and often result in unexpected side effect.Therefore, there is a demand for the development of pharmaceuticals thathave low affinity for CYP and between which causes little concern aboutinteractions between other medicines.

As conventional nonpeptide compounds that selectively stimulate V₂receptor and show antidiuretic effects, tricyclic compounds representedby the general Formula (A), general Formula (B), or general Formula (C)are disclosed in WO 99/06409, WO 99/06403, and WO 00/46224.

(Each symbol is as defined in the above publications.)

Additionally, condensed azepine derivatives represented by the generalFormula (D) are disclosed in WO 01/49682.

(Each symbol is as defined in the above publication.)

Also, benzazepine derivatives represented by the general Formula (E) aredisclosed in WO 97/22591 and Japanese Patent No. 2926335, andbenzoheterocyclic compounds represented by the general Formula (F) orgeneral Formula (G) are disclosed in Japanese Patent No. 3215910, andJapanese Patent Publication Nos. tokkaihei 11-349570 and tokkai2000-351768.

(Each symbol is as defined in the above publications.)

However, none of the publications discloses4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivatives.

In addition, although WO 95/06035 and WO 98/39325, and Japanese PatentPublication No. tokkaihei 9-221475 disclose4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivatives that haveAVP receptor antagonist effects or oxytocin receptor antagonist effects,none of them discloses V₂ receptor agonist effects and efficacy intreating central diabetes insipidus and nocturia.

Accordingly, there is a demand for the development of a nonpeptideantidiuretic agent that is useful in the treatment of central diabetesinsipidus and/or nocturia, and has high biological availability.

DISCLOSURE OF THE INVENTION

The inventors, as a result of assiduous studies on compounds having V₂receptor agonist effects and efficacy in treating central diabetesinsipidus and/or nocturia, discovered that4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin derivatives have sucheffects, and completed the present invention. Additionally, theinventors discovered that the compound of the present invention has avery low inhibitory activity against medicine metabolism enzymes ofCYP3A4 and CYP2C9, compared with known benzazepine derivatives having V₂receptor agonist activity, and completed the present invention.

The object of the present invention is, to provide a novel4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative representedby the following general Formula (I) or a pharmaceutically acceptablesalt thereof, which are useful for a drug for the treatment of centraldiabetes insipidus and/or nocturia; and a drug comprising the compoundas an active ingredient, particularly a drug for the treatment ofcentral diabetes insipidus or nocturia, or a drug as argininevasopressin V₂ receptor agonist.

-   -   wherein each symbol has the following meaning:    -   R¹: —OH, —O-lower alkyl, or an optionally substituted amino;    -   R²: a lower alkyl which may be substituted with one or more        halogen, or a halogen;    -   R³, R⁴: one is —H, a lower alkyl, or a halogen, and the other is        an optionally substituted nonaromatic cyclic amino, or an        optionally substituted aromatic cyclic amino; and    -   R⁵: —H, a lower alkyl, or a halogen.

The compound of the present invention is characterized by having twofluoro groups on a carbon atom in a benzazepine ring, which carbon atomis adjacent to a carbon atom substituted by substituted methylidenegroup in the ring. Further, since the double bond conjugated with acarbonyl group is not isomerized due to the two fluoro groups, thecompound of the invention has a sufficient stability even in a livingbody.

Preferred is a novel 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepinederivative represented by the general Formula (I) or a pharmaceuticallyacceptable salt thereof, wherein R¹ is a group represented by thegeneral Formula (II), or a group represented by the general Formula(III).

-   -   wherein each symbol has the following meaning:    -   A: a single bond, lower alkylene, or -lower alkylene-C(═O)—;    -   R¹¹: a lower alkyl which may be substituted with a group        selected from the group consisting of —OH, —O-lower alkyl,        —CO₂H—, —CO₂-lower alkyl, and carbamoyl which may be substituted        with one or two lower alkyl, or —H;    -   R¹²: (1) when A is a single bond or lower alkylene, R¹² is aryl,        cycloalkyl, aromatic heterocycle, or nonaromatic heterocycle,        each of which may be substituted, or —H, —OH, —O-lower alkyl,        —CO₂H, —CO₂-lower alkyl, or carbamoyl which may be substituted        with one or two lower alkyl.    -   (2) when A is -lower alkylene-C(═O)—, R¹² is a group represented        by the general Formula (III), or a group represented by the        general Formula (IV);    -   B: a single bond or lower alkylene;    -   R¹³, R¹⁴: optionally substituted nonaromatic cyclic amino group        bonded together with an adjacent nitrogen atom.

More preferred is a novel4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative representedby the general Formula (I) or a pharmaceutically acceptable saltthereof, wherein R¹ is a group represented by the general Formula (II),or a group represented by the general Formula (III); R³ is an optionallysubstituted nonaromatic cyclic amino group, or an optionally substitutedaromatic cyclic amino group; R⁴ is —H, a lower alkyl, or a halogen; andR⁵ is —H.

Still more preferred is a novel4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative representedby the general Formula (I) or a pharmaceutically acceptable saltthereof, wherein R¹ is a group represented by the general Formula (II),or a group represented by the general Formula (III); R³ is an optionallysubstituted nonaromatic cyclic amino, or an optionally substitutedaromatic cyclic amino; R⁴ is —H; and R⁵ is —H.

Most preferred is a novel4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative representedby the general Formula (I) or a pharmaceutically acceptable saltthereof, wherein R¹ is a group represented by the general Formula (II),or a group represented by the general Formula (III); R³ ismethylpyrazolyl, pyrrolidinyl, or methylpyrrolidinyl; R⁴ is —H; and R⁵is —H.

Among these compounds, a compound or a pharmaceutically acceptable saltthereof selected from the compound group A and the compound group B areparticularly preferable, and a compound or a pharmaceutically saltthereof selected from the compound group A are more preferable.

The compound group A includes:

-   (2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazoly-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}-N-(pyridin-2-ylmethyl)acetamide;-   (2Z)-N-(2-amino-2-oxoethyl)-2-[1-(2-chloro-4-pyrrolidin-1-ylbenzoyl)-4,4-difluoro-1,2,    3,4-tetrahydro-5H-1-benzazepin-5-ylidene] acetamide;-   (2Z)-2-{4,4-difluoro-1-[4-(3-methyl-1H-pyrazol-1-yl)-2-(trifluoromethyl)benzoyl]1-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetamide;-   (2Z)-N-(2-amino-2-oxoethyl)-2-{4,4-difluoro-1-[4-(3R)-3-methylpyrrolidin-1-yl]-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetamide;-   (2Z)-2-{4,4-difluoro-1-[4-[(3R)-3-methylpyrrolidin-1yl]    2-(trifluoromethyl)benzoyl]-1,2,    3,4-tetrahydro-5H-1-benzazepin-5-ylidene}-N-(2-hydroxyethyl)acetamide;-   (2Z)-N-(2-amino-2-oxoethyl)-2-{4,4-difluoro-1-[4-(3S)-3-methylpyrrolidin-1-yl]-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetamide;-   (2Z)-2-{4,4-difluoro-1-[4-[(3-methyl-1H-pyrazol-1-yl)-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene]-N-(2-hydroxyethyl)acetamide;-   (2Z)-N-(2-amino-2-oxoethyl)-2-(1-{2-chloro-4-[(3R)-3-methylpyrrolidin-1-yl]benzoyl}-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene)    acetamide;-   (2Z)-N-(2-amino-2-oxoethyl)-2-(1-{2-chloro-4-[(3S)-3-methylpyrrolidin-1-yl]benzoyl}-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene)acetamide;-   (2Z)-2-{4,4-difluoro-1-[4-(4-methyl-1H-pyrazol-1-yl)-2-(trifluoromethyl)benzoyl]-1,    2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetamide;-   (2Z)-N-(2-amino-2-oxoethyl)-2-{1-[4-(3,4-dimethylpyrrolidin-1-yl)-2-(trifluoromethyl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetamide;    and-   (2Z)-2-{4,4-difluoro-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetamide.

The compound group B includes:

-   (2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,    3,4-tetrahydro-5H-1-benzazepin-5-ylidene}-N-[3-(hydroxymethyl)phenyl]acetamide;-   (2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,    3,4-tetrahydro-5H-1-benzazepin-5-ylidene}-N-[4-(hydroxymethyl)phenyl]acetamide;-   (2Z)-2-{1-[2-chloro-4-(3-methyl    1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,    3,4-tetrahydro-5H-1-benzazepin-5-ylidene}-N-[(6-methylpyridin-2-yl)methyl]acetamide;-   3-[((2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,    3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetyl)amino]benzamide;-   4-[((2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetyl)amino]benzamide;-   4-{[((2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,    3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetyl)amino]methyl}benzamide;-   (2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,    3,4-tetrahydro-5H-1-benzazepin-5-ylidene}-N-[3-(methoxymethyl)phenyl]acetamide;-   (2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}-N-[3-(1-hydroxyethyl)phenyl]    acetamide;-   (2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}-N-[3-(methylsulfonyl)phenyl]acetamide;-   (2Z)-N-(3-acetylphenyl)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetamide;-   (2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,    3,4-tetrahydro-5H-1-benzazepin-5-ylidene}-N-(3-methylphenyl)acetamide;-   (2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,    3,4-tetrahydro-5H-1-benzazepin-5-ylidene}-N-(3-fluorophenyl)acetamide;-   (2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}-N-[3-(2-hydroxyethyl)phenyl]    acetamide;-   (2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}-N-(2-hydroxy-1,1-dimethyletyl)    acetamide;-   1-((2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,    3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetyl)piperidine-3-carboxamide;-   (2Z)-N-[4-(aminosulfonyl)benzyl]-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,    3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetamide;-   (2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,    3,4-tetrahydro-5H-1-benzazepin-5-ylidene}-N-(2-hydroxycyclohexyl)acetamide;-   (2Z)-N-[3-(2-amino-2-oxoethyl)phenyl]-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,    3,4-tetrahydro-5H-1-benzazepin-5-yliende}acetamide;-   3-{3-[((2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-yliende}acetyl)amino]phenyl}propanamide;-   (2E)-3-{3-[((2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,    3,4-tetrahydro-5H-1-benzazepin-5-yliende}acetyl)amino]phenyl}acrylamide;-   (2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,    3,4-tetrahydro-5H-1-benzazepin-5-yliende}-N-(2-oxopyrrolidin-3-yl)acetamide;-   (2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,    3,4-tetrahydro-5H-1-benzazepin-5-yliende}-N-(2-oxotetrahydrofuran-3-yl)acetamide;-   3-[((2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,    3,4-tetrahydro-5H-1-benzazepin-5-yliende}acetyl)amino]-N-methylbenzamide;-   (2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-yliende}-N-{2-[2-(hydroxymethyl)piperidin-1-yl]-2-oxoethyl}acetamide;-   (2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,    3,4-tetrahydro-5H-1-benzazepin-5-yliende}-N-{2-[3-(hydroxymethyl)piperidin-1-yl]-2-oxoethyl}acetamide;-   (2Z)-N-[3-(acetylamino)phenyl]-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-yliende}acetamide;-   (2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-yliende}-N-(2-oxotetrahydrothiophen-3-yl)acetamide;-   (2Z)-2-{1-[2-chloro-4-(3,3-dimethylpyrrolidin-1-yl)benzoyl]-4,4-difluoro-1,2,    3,4-tetrahydro-5H-1-benzazepin-5-yliende}-N-(pyridine-2-ylmethyl)acetamide;-   (2Z)-2-{1-[2-chloro-4-(3,3-dimethylpyrrolidin-1-yl)benzoyl]-4,4-difluoro-1,2,    3,4-tetrahydro-5H-1-benzazepin-5-yliende}acetamide;-   (2Z)-N-(2-amino-2-oxoethyl)-2-{1-[2-chloro-4-(3-ethyl-3-methylpyrrolidin-1-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-yliende}acetamide;-   (2Z)-N-(2-amino-2-oxoethylyl)-2-{1-[2-chloro-4-(3,3-dimethylpyrrolidin-1-yl)benzoyl]-4,4-diflubro-1,    2, 3, 4-tetrahydro-5H-1-benzazepin-5-yliende}acetamide;-   (2Z)-N-(2-amino-2-oxoethylyl)-2-{1-[2-chloro-4-(3-phenylpyrrolidin-1-yl)benzoyl]-4,4-difluoro-1,    2, 3, 4-tetrahydro-5H-1-benzazepin-5-yliende}acetamide;-   (2Z)-2-{1-[2-chloro-4-(3,3-dimethylpyrrolidin-1-yl)benzoyl]-4,4-difluoro-1,2,    3,4-tetrahydro-5H-1-benzazepin-5-yliende}-N-(2-hydroxyethyl)    acetamide;-   (2Z)-2-{1-[2-chloro-4-(3-phenylpyrrolidin-1-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-yliende}acetamide;-   (2Z)-2-{1-[2-chloro-4-(3-ethyl-3-methylpyrrolidin-1-yl)benzoyl]-4,4-difluoro-1,    2,3,4-tetrahydro-5H-1-benzazepin-5-yliende}acetamide;-   (2Z)-2-{4,4-difluoro-1-[4-[(3R)-3-methylpyrrolidin-1-yl]-2-(trifluoromethyl)benzoyl]-1,    2,3,4-tetrahydro-5H-1-benzazepin-5-yliende}-N-(2-hydroxyethyl)acetamide;-   (2Z)-2-{4,4-difluoro-1-[4-[(3R)-3-methylpyrrolidin-1-yl]-2-(trifluoromethyl)benzoyl]-1,    2,3,4-tetrahydro-5H-1-benzazepin-5-yliende}acetamide;-   (2Z)-2-{1-[2-chloro-5-fluoro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,    3,4-tetrahydro-5H-1-benzazepin-5-yliende}acetamide; and-   (2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,    2,3,4-tetrahydro-5H-1-benzazepin-5-yliende}-N-[4-(1,2-dihydroxyethyl)phenyl]acetamide.

Another object of the present invention is to provide a novel4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative representedby the following general Formula (V) or a pharmaceutically acceptablesalt thereof, which is a useful intermediate in the preparation of the4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative representedby the above general Formula (I) or a pharmaceutically acceptable saltthereof, which is useful in the treatment of central diabetes insipidusand/or nocturia.

-   -   wherein each symbol has the following meaning,    -   R²¹: lower alkyl,    -   R²²: chloro or trifluoromethyl,    -   R²³, R²⁴: one is —H, and the other is an optionally protected        hydrazino group, and    -   R²¹ is preferably methyl or ethyl, more preferably methyl.

The present invention will be explained in detail herein below.

In the definition of the general formula for the compound of the presentinvention, the term “lower alkyl” means a monovalent group of a straightor branched carbon chain having 1 to 6 carbon atoms, and its examplesinclude methyl, ethyl, propyl, butyl, pentyl, and hexyl, and structuralisomers thereof such as isopropyl, tert-butyl, and the like, of whichalkyl having 1 to 3 carbon atoms such as methyl, ethyl, propyl, andisopropyl are preferred.

The term “lower alkenyl” means a monovalent group of a straight orbranched unsaturated carbon chain having 2 to 6 carbon atoms, and itsexamples include vinyl, allyl, 1-butenyl, 2-butenyl, 1-hexenyl, and3-hexenyl, and structural isomers thereof such as 2-methylallyl, and thelike, of which vinyl and allyl are preferred.

The term “lower alkylene” means a divalent group of a straight orbranched carbon chain having 1 to 6 carbon atoms, and its examplesinclude methylene, ethylene, trimethylene, methylmethylene,methylethylene, dimethylmethylene, and the like.

The “cycloalkyl” means a monovalent group of a nonaromatic hydrocarbonring having 3 to 8 carbon atoms, which may have a partial unsaturation,and its examples include cyclopropyl, cyclopentyl, cyclohexyl,cyclooctyl, cyclohexenyl, cyclooctandienyl, and the like.

The term “aryl” means a monovalent group of a mono- to tri-cyclicaromatic hydrocarbon ring having 6 to 14 carbon atoms, and its examplesinclude phenyl, naphthyl, and the like, of which phenyl is preferred.

The term “aromatic heterocycle” means a monovalent group of a mono- totri-cyclic aromatic ring having a hetero atom such as a nitrogen atom,an oxygen atom, a sulfur atom, and the like, and its examples includepyridyl, thienyl, furyl, benzimidazolyl, pyrazinyl, pyridazinyl,thiazolyl, pyrimidinyl, benzothiazoyl, pyrazolyl, indazolyl, pyrrolyl,oxazoyl, triazoyl, tetrazoyl, indolyl, quinolyl, isothiazolyl,isooxazoyl, imidazoyl, and the like, of which pyridyl is preferred.

The term “nonaromatic heterocycle” means a monovalent group of a five-to seven-membered ring having a hetero atom such as a nitrogen atom, anoxygen atom, a sulfur atom, and the like, which may have a partialunsaturation and may be condensed with an aryl or aromatic heterocycle,and its examples include pyrrolidinyl, imidazolydinyl, piperidinyl,piperazinyl, azepinyl, morphonyl, thiomorphonyl, tetrahydrofuryl,tetrahydrothienyl, and the like, of which pyrrolidinyl, tetrahydrofuryl,and tetrahydrothienyl are preferred.

The term “aromatic cyclic amino” means a monovalent group of a five- toseven-membered aromatic cyclic amine, which may contain a nitrogen, anoxygen, or a sulfur atom, and its examples include benzimidazolyl,indolyl, pyrazolyl, indazolyl, pyrrolyl, imidazolyl, and the like, ofwhich pyrazolyl is preferred.

The term “nonaromatic cyclic amino” means a monovalent group of a three-to ten-membered, preferably a five- to seven-membered nonaromatic cyclicamine, which may have a partial unsaturation and comprise a nitrogen, anoxygen or a sulfur atom, and its examples include pyrrolidinyl,piperidinyl, azepinyl, morphonyl, thiomorphonyl, piperazinyl,pyrazolidinyl, indolinyl, isoindolinyl, dihydropyrrolyl, pyrrolinyl,dihydropyrrolinyl, and the like, of which pyrrolidinyl, piperidinyl, anddihydropyrrolyl are preferred.

The term “halogen” means a monovalent group of a halogen atom, and itsexamples include fluoro, chloro, bromo, iodo, and the like.

As the substituent group that can be used for the term “optionallysubstituted” or “which may be substituted”, those which are commonlyused as a substituent group for each corresponding group can be used,and each group may have one or more substituent groups.

In the definition of R¹, the “optionally substituted amino group”includes the groups represented by the above general Formulae (II) and(III).

As the substituent groups that can be used for “aryl, cycloalkyl,aromatic heterocycle, or nonaromatic heterocycle, each of which may besubstituted” in the definition of R¹², and “optionally substitutednonaromatic cyclic amino group” and “optionally substituted aromaticcyclic amino group” in the definition of R¹³, R¹⁴, R³, and R⁴, thefollowing groups (a) to (h) can be exemplified. R^(A) is a lower alkylgroup which may be substituted with one or more groups selected from thegroup consisting of —OH, —O-lower alkyl, an amino which may besubstituted with one or two lower alkyls, a carbamoyl which may besubstituted with one or two lower alkyls, an aryl, an aromaticheterocycle and a halogen.

-   (a) halogen;-   (b) —OH, —O—R^(A), —O-aryl, —OCO—R^(A), oxo(=O);-   (c) —SH, —S—R^(A), —S-aryl, —SO—R^(A), —SO-aryl, SO₂—R^(A),    —SO₂-aryl, sulfamoyl which may be substituted with one or two R^(A);-   (d) amino which may be substituted with one or two R^(A),    —NHCO—R^(A)c, —NHCO-aryl, —NHSO₂—R_(A), —NHSO₂-aryl, nitro;-   (e) —CHO, —CO—R_(A), —CO₂H, —CO₂—R_(A), carbamoyl which may be    substituted with one or two R_(A), cyano;-   (f) aryl or cycloalkyl, each of which may be substituted with one or    more groups selected from the group consisting of —OH, —O-lower    alkyl, amino which may be substituted with one or two lower alkyls,    carbamoyl which may be substituted with one or two lower alkyls,    aryl, aromatic heterocycle, halogen and R_(A);    -   (g) aromatic heterocycle or nonaromatic heterocycle, each of        which may be substituted with one or more groups selected from        the group consisting of —OH, —O-lower alkyl, amino which may be        substituted with one or two lower alkyls, carbamoyl which may be        substituted with one or two lower alkyls, aryl, aromatic        heterocycle, halogen and R_(A);    -   (h) lower alkyl or lower alkenyl, each of which may be        substituted with one or more groups selected from the        substituent groups described in (a) to (g).

As a protection group that can be used for “optionally protectedhydrazino group” in the definition of R²³ and R²⁴, those which arecommonly used as a protection group for an amino group can be used, andthose described in “Protective Groups in Organic Synthesis”, thirdedition, edited by Greene and Wuts, can be exemplified. Its examplesinclude acetyl, methoxycarbonyl, ethoxycarbonyl, tert-butyloxycarbonyl,benzyloxycarbonyl, phthalimide, and the like, of whichtert-butyloxycarbonyl is preferred.

The compound represented by the general Formula (I) may compriseasymmetric carbon atoms according to the kinds of substituent groups,and optical isomers based on the asymmetric carbon atom may exist. Thecompound of the present invention includes a mixture of these opticalisomers or isolated ones. Also, tautomers may be included in thecompound of the present invention, and the compound of the presentinvention includes these isomers as a mixture or as an isolated one.

In addition, the compound of the present invention may form a salt,which is included in the present invention as long as pharmaceuticallyacceptable. Examples of the salt include addition salts with a mineralacid such as hydrochloric acid, hydrobromic acid, hydroiodic acid,sulfuric acid, nitric acid, phosphoric acid, and the like, or an organicacid such as formic acid, acetic acid, propionic acid, oxalic acid,malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid,malic acid, tartaric acid, citric acid, methanesulfonic acid,ethanesulfonic acid, p-toluenesulfonic acid, aspartic acid, glutamicacid, and the like; salts with an inorganic base such as sodium,potassium, magnesium, calcium, and the like, or an organic base such asmethylamine, ethylamine, ethanolamine, lysine, ornithine, and the like;and ammonium salts, and the like. And, a hydrate and a solvate of thecompound and its pharmaceutically acceptable salt of the presentinvention, and those having polymorphism, are also included in thepresent invention. In addition, the compound of the present inventionalso includes a compound which is metabolized in a living organism to beconverted into the compound of the general Formula (I) or the saltthereof, a so-called prodrug. As a group for forming the prodrug, thosedescribed in Prog. Med., 5; 2157-2161, 1985. and Hirokawa Shoten, 1990,“Development of medicine” Vol. 7, Molecular Design, pp 163-198 can beexemplified.

(Production Methods)

The compound and its pharmaceutically acceptable salt can be prepared byvarious known synthesis methods, using characteristics based on itsbasic backbone or the kinds of substituent groups. The Representativepreparation methods will be explained in detail. And, according to thekinds of functional groups, it is advantageous in some cases in terms ofpreparation technique to substitute a functional group with a suitableprotection group, i.e., a group that can be easily converted into thefunctional group, in the step of a preparation of raw material orintermediate. Then, if necessary, the protection group is removed toobtain a desired compound. Examples of the functional group includehydroxyl, carboxy, and amino groups, and examples of the protectiongroup include those described in “Protective Groups in OrganicSynthesis”, third edition, edited by Greene and Wuts. It is preferableto suitably use them depending on reaction conditions.

<First Production Method>

(First Step)

-   -   (wherein R², R³, and R⁴ are as defined in the foregoing; and one        of X and Y is —H, a lower alkyl, or a halogen, and the other is        a leaving group or an amino group.)

In this step, a leaving group of X or Y in the compound (1a) issubstituted with an optionally substituted nonaromatic cyclic amine oraromatic cyclic amine (“(1b)”) to prepare a compound (1c), or an aminogroup of X or Y is converted into a pyrrol-1-yl group. Examples of theleaving group of X or Y include a halogen atom, methylsulfonyl,1H-benzotriazol-1-yloxy, methanesulfonyloxy, p-toluenesulfonyloxy, andtrifluoromethanesulfonyloxy.

When one of R³ and R⁴ is pyrrole, one of X and Y is an amino group, andin this case, the compound (1c) can be synthesized with reference to J.Med. Chem., 28(10), 1405, 1985.

And, when X or Y is a leaving group, preferably I, Br, ortrifluoromethanesulfonyloxy, the compound (1c) can be synthesized by acoupling reaction using Pd(0). The coupling reaction can be conductedwith reference to Tetrahedron Letters, Vol. 38, No. 66, pp. 6359-662,1997.

And, when X is a leaving group, preferably F or Cl, the compound (1c)can be synthesized by a substitution reaction. The reaction can becarried out free of a solvent or in an inert solvent including anaromatic hydrocarbon such as benzene, toluene, xylene, and the like; anether such as diethylether, tetrahydrofuran (THF), dioxane, and thelike; a halogenated hydrocarbon such as dichloromethane,1,2-dichloroethane, chloroform, and the like; N,N-dimethylformamide(DMF); dimethylacetamide (DMA); N-methylpyrrolidone; dimethylsulfoxide(DMSO); an ester such as ethyl acetic acid (EtOAc); acetonitrile, andthe like, or an alcohol solvent such as methanol (MeOH), ethanol (EtOH),2-propanol, and the like, at room temperature or while heating underreflux, using equal moles of the compound (1a) and the compound (1b) oran excess amount of any one of them.

Depending on the compounds to be produced, it is advantageous to carryout the reaction in the presence of an organic base (preferably,triethylamine, diisopropylethylamine, N-methylmorpholin, pyridine,4-(N,N-dimethylamino)pyridine), or a basic metal salt (preferablypotassium carbonate, cesium carbonate, sodium hydroxide, or sodiumhydride). And, when one of R³ and R⁴ is an optionally substitutedpyrazolyl group, the substitution reaction may be carried out using anoptionally protected hydrazine, preferably a hydrazine protected withmono tert-butyl oxycarbonyl instead of the compound (1b), and then, ifnecessary, the protection group is removed to react the aldehydeprotected form of acylacetaldehyde (e.g., acetylacetaldehydedimethylacetal) to form an optionally substituted pyrazol ring. Theformation of the pyrazol ring is advantageously carried out in thepresence of acid, preferably hydrochloric acid, trifluoroacetic acid,p-toluenesulfonic acid, and the like), under room temperature or withheating.(Second Step)

In this step, the compound (1c) obtained in the first step of the firstproduction method is hydrolyzed to prepare a compound (1d).

The reaction can be carried out in a solvent inert to the compound (1c),such as an aromatic hydrocarbon, an ether, a halogenated hydrocarbon, analcohol, DMF, DMA, DMSO, pyridine, water, and the like, in the presenceof a mineral acid such as sulfuric acid, hydrochloric acid, hydrobromicacid, an organic acid such as formic acid, acetic acid, and the like, ora base such as sodium hydroxide, potassium hydroxide, potassiumcarbonate, sodium carbonate, cesium carbonate, or ammonia, under acooling to a heat refluxing environment. Reaction temperature can beappropriately selected depending on the compounds.(Third Step)

-   -   (wherein R⁵ is as defined in the foregoing.)

In this step, a compound (1f) of the present invention is prepared bythe amidation of the compound (1d) obtained in the second step of thefirst production method or its reactive derivative with a compound (1e).

As the reactive derivative of the compound (1d), a common ester such asmethylester, ethylester, tert-butyl ester, and the like; an acid halidesuch as acid chloride, acid bromide, and the like; an acid azide; anactive ester with N-hydroxybenzotriazole, p-nitrophenol, orN-hydroxysuccinimide, and the like; a symmetrical acid anhydride; anacid anhydride mixture of an alkyl halide carbonate, and the like, andan halocarboxylic acid alkylester, pivaloyl halide, p-toluenesulfonicacid chloride, and the like; and a phosphate-type acid anhydride mixtureobtained by the reaction of diphenylphosphoryl chloride andN-methylmorpholin can be used.

And, when the compound (1d) is used in its free acid form or an activeester without isolation, it is preferable to use a condensing agent suchas dicyclohexylcarbodiimide (DCC), 1,1′-carbonylbis-1H-imidazole(CDI),diphenylphosphorylazide (DPPA), diethylphosphorylcyanide, and1-ethyl-3-(3-dimehtylaminopropyl)carbodiimide hydrochloride (EDCI HCl),and the like.

Particularly, in the present invention, an acid chloride method, amethod of carrying out the reaction in the presence of both an activeesterification agent and a condensing agent, or a method of treating acommon ester with an amine is convenient because it is easy to preparethe compound of the present invention therewith. The reaction is,although it varies depending on the employed reactive derivative orcondensing agent, carried out in an inert organic solvent such as ahalogenated hydrocarbon, an aromatic hydrocarbon, an ether, an ester,acetonitrile, DMF, or DMSO, and the like, under a cooling, a cooling toroom temperature, or a room temperature to heating environment.

In carrying out the reaction, in order to progress the reactionsmoothly, it is advantageous in some cases to use the compound (1e) inan excess amount or to carry out the reaction in the presence of a basesuch as N,N-dimethylaniline, pyridine, 4-(N,N-dimethylamino)pyridine,picoline, lutidine, and the like. And, a salt consisting of a strongacid and a weak base such as pyridine hydrochloride, pyridine,p-toluenesulfonate, N,N-dimethylaniline hydrochloride, and the like canbe used. Pyridine can also be used as a solvent.

Particularly, it is preferable to carry out the reaction in a solventsuch as acetonitrile, DMF, and the like, in the presence of a base suchas pyridine, N,N-dimethylaniline, and the like, or a salt such aspyridine hydrochloride, and the like.(Fourth Step)

-   -   (wherein NRR′ is an optionally substituted amino, preferably a        group represented by the general Formula (II) of (III).)

In this step, a compound (1f) of the present invention obtained in thethird step of the first production method is hydrolyzed to prepare acompound (1g) of the present invention, and then the compound (I) of thepresent invention is prepared by the amidation of the compound (1g) orits reactive derivative with a compound (1h).

Each reaction can be carried out in accordance with the second step orthird step of the first production method.<Second Production Method>

In this method, a compound (1e) is hydrolyzed in a first step to preparea compound (2a), a compound (2b) is prepared by the amidation of thecompound (2a) or its reactive derivative with a compound (1 h) in asecond step, and then the compound (I) is prepared by the amidation ofthe compound (2b) with a compound (1d) or its reactive derivative in athird step.

The reaction in the first step can be carried out in accordance with thesecond step of the first production method, and the reactions in thesecond and third steps in accordance with the third step of the firstproduction method.<Third Production Method>

In this method, a compound (3b) is prepared by the amidation of thecompound (2b) obtained in the second step of the second productionmethod with a compound (3a) or its reactive derivative in a first step,and in a second step, a leaving group of X or Y of the obtained compound(3b) is substituted with a compound (1b) or an optionally substitutedhydrazine to form an optionally substituted pyrazole ring, as shown inthe first step of the first production method, thereby forming acompound (I) of the present invention. The leaving group of X or Y is asdefined in the first step of the first production method.

The reaction in the first step can be carried out in accordance with thethird step of the first production method, and the reaction in thesecond step in accordance with the first step of the first productionmethod.<Fourth Production Method>

In this method, a compound (4a) is prepared by the amidation of acompound (1e) with a compound (3a) or its reactive derivative in a firststep, the obtained compound (4a) is hydrolyzed to prepare a compound(4b) in a second step, and a compound (3b) is prepared by the amidationof the obtained compound (4b) or its reactive derivative with a compound(1h) in a third step, and then, in a fourth step, the leaving group of Xor Y of the obtained compound (3b) is substituted with a compound (1b)or an optionally substituted hydrazine to form an optionally substitutedpyrazole ring, as shown in the first step of the first productionmethod, thereby preparing a compound (I) of the present invention. Theleaving group of X or Y is as defined in the first step of the firstproduction method.

The reactions in the first and third steps can be carried out inaccordance with the third step of the first production method, thereaction in the second step in accordance with the second step of thefirst production method, and the reaction in the fourth step inaccordance with the first step of the first production method.<Fifth Production Method>

In this method, in a first step, the leaving group of X or Y of thecompound (4a) obtained in the first step of the fourth production methodis substituted with a compound (1b) or an optionally substitutedhydrazine to form an optionally substituted pyrazole ring, as shown inthe first step of the first production method, thereby forming acompound (1f) of the present invention, which is hydrolyzed to prepare acompound (1g) of the present invention in a second step, and then thecompound (I) of the present invention is prepared by the amidation ofthe compound (1g) or its reactive derivative with a compound (1h) in athird step. The leaving group of X or Y is as defined in the first stepof the first production method.

The reaction in the first step can be carried out in accordance with thefirst step of the first production method, the reaction in the secondstep in accordance with the second step of the first production method,and the reaction in the third step in accordance with the third step ofthe first production method.

The thus produced compound of the present invention is isolated andpurified as its free form or as a salt thereof. A salt of the compound(I) can be produced by subjecting it to a usual salt formation reaction.The isolation and purification are carried out by usual chemicalmanipulations such as extraction, concentration, evaporation,crystallization, filtration, recrystallization, various types ofchromatography, and the like.

Various types of isomers can be separated by usual method using thedifference in physicochemical properties among isomers. For example,racemic compounds can be separated by a general racemic compoundresolution method, e.g., a method in which racemic compounds areconverted into diastereomer salts with an optically active base such astartaric acid, and the like and then subjected to optical resolution.And, diastereomers can be separated by fraction crystallization orvarious types of chromatography or the like. Also, optically activecompounds can be prepared using appropriate optically active startingmaterials.

The compound and its salt of the present invention have excellentstimulation effects for arginine vasopressin V₂ receptors. Thus, thecompound of the present invention has antidiuretic effects and effectsof releasing blood coagulating agents VIII factor and von Willebrandfactor, is useful for treating various urination disorders, polyuria, orhemorrhage conditions, and is effective in the diagnosis, prevention,and treatment of polyuria, urinary incontinence, central diabetesinsipidus, nocturia, nocturnal enuresis, spontanous hemorrhage,hemophilia, von Willebrand disease, uremia, congenital or acquiredplatelet dysfunction, traumatic or surgical hemorrhage, hepatocirrhosis,and the like.

Since the compound of the present invention has little inhibitioneffects against medicine metabolism enzymes CYP3A4 and CYP2C9, there isless concern for interaction with other medicines metabolized by CYP3A4or CYP2C9, compared with known benzazepine derivatives having argininevasopressin V₂ receptor agonist effects, and it can be safely used incombined therapy with various preparations.

Examples of medicines metabolized by CYP3A4 include simvastatin,lovastatin, fluvastatin, midazolam, niphedipine, amlodipine,nicardipine, and the like, and example of medicines metabolized byCYP2C9 include diclofenac, ibuprofen, indomethacin, tolbutamide,glibenclamide, losartan, and the like (General Clinic, 48(6), 1427-1431,1999).

Pharmaceutical efficacy of the compound of the present invention wasconfirmed by the following assays.

(1) V₂ Receptor Binding Assay

A human V₂ expression CHO cell membrane sample was prepared inaccordance with a method of Tahara, et al. (British Journal ofPharmacology. Vol 125, p. 1463-1470, 1998). 2 μg of the membrane samplewere incubated in a total of 250 μl of 50 mM tris-chloric acid buffersolution (pH=7.4) containing 10 mM MgCl₂ and 0.1% bovine serum albumin(BSA), together with [³H]-Arginine-Vasopressin (hereinafter referred toas ‘[³H]-Vasopressin’) (0.5 nM, Specific activity=75 Ci mmol) and a testcompound (10⁻¹⁰˜10⁻⁵ M) at 25° C. for 60 minutes. Then, free[³H]-Vasopressin and receptor binding [³H]-Vasopressin were separatedusing a cell harvester, and the receptor binding [³H]-Vasopressin wasadsorbed on a Unifilter Plate GF/B glass filter, sufficiently dried, andthen mixed with a microplate scintillation cocktail. The amount ofreceptor binding [³H]-Vasopressin was measured using a top count, andinhibition rate was calculated by the following equation.Inhibition Rate(%)=100−(C ₁ −B ₁)/(C ₀ −B ₁)×100

-   C₁: the amount of [³H]-Vasopressin bound to the membrane sample,    when the receptor membrane sample is treated in the coexistence of a    test compound of known concentration and [³H]-Vasopressin-   C₀: the amount of [³H]-Vasopressin bound to the membrane sample,    when the receptor membrane sample is treated with [³H]-Vasopressin,    in the absence of a test compound-   B₁: the amount of [³H]-Vasopressin bound to the membrane sample,    when the receptor membrane sample is treated in the coexistence of    an excess amount of Vasopressin (10⁻⁶ M) and [³H]-Vasopressin

From the above equation, concentration of the test compoundcorresponding to the inhibition rate of 50% (IC₅₀) was calculated, fromwhich affinity of the test compound for a receptor, i.e., dissociationcoefficient (Ki) was calculated by the following equation.Dissociation Coefficient (Ki)=IC₅₀/(1+[L]/Kd)

-   [L]: the concentration of [³H]-Vasopressin

Kd: dissociation coefficient of [3H]-Vasopressin for the receptor,calculated from saturation binding assay TABLE 1 [Affinity for V₂receptor] Compound Ki (nM) Compound Ki (nM) Example 72 3.7 Example 584.8 Example 76 2.2 Example 74 5.6 Example 119 5.6 Control 68

As the control, the compound of Example 32 described in WO 97/22591(Compound name:2-[(5R)-1-(2-chloro-4-pyrrolidin-1-ylbenzoyl)-2,3,4,5-tetrahydro-1H-1-benzazepin-5-yl]-N-isopropyacetamide)was used.

As shown in Table 1, it has been verified that the compound of thepresent invention has high affinity for the V₂ receptor.

(2) Antidiuresis Assay (Intravenous Administration)

For the assay, 5 Wistar male rats (10˜12 weeks of age) were employed foreach group. For group A, 0.3 mg/kg of the compound of Example 135, forgroup B, 0.3 mg/kg of the compound of Example 201, and for group C, 1ml/kg of physiological saline solution comprising DMSO as a control wereintravenously administrated. After 15 minutes, 30 ml/kg of distilledwater were orally administrated (water load). Until 2 hours after thewater load, urine was collected in a metabolism cage, and the amount ofurine when the water load is set to 100% was calculated as the urinaryexcretion rate. For the assay, the average value in each group ofurinary excretion rate until 1 hour after the water load and that until2 hours after the water load was employed. The results are described inthe following Table 2. TABLE 2 [Antidiuretic effects (intravenousadministration)] Urinary excretion rate (%) Compound After 1 hour After2 hours Group A Example 135 0 1.1 Group B Example 201 0 13.3 Group CDMSO 49.9 58.4

As shown in Table 2, it has been verified that the compound of thepresent invention has excellent antidiuretic effects.

(3) Antidiuresis Assay (Oral Administration)

For the assay, Wistar male rats (10˜12 weeks of age) were employed. Thetest compound was orally administrated, and after 15 minutes, 30 ml/kgof distilled water were orally administrated (water load). Until 4 hoursafter the water load, urine was collected in a metabolism cage, and theamount of urine when the water load was set to 100% was calculated asthe urinary excretion rate. For the assay, the amount of the testcompound required for decreasing urinary excretion rate by 50% (ED₅₀)was employed. The results are described in the following Table 3. TABLE3 [Antidiuretic effects (oral administration)] Compound ED₅₀ (mg/kg)Compound ED₅₀ (mg/kg) Example 139 0.14 Example 174 0.17 Example 76 0.22Example 173 0.16 Example 175 0.38

As shown in Table 3, it has been verified that the compound of thepresent invention has excellent antidiuretic effects by oraladministration as well as by intravenous administration.

(4) Cytochrome P450 (3A4) Enzyme Inhibition Assay

The assay was carried out in accordance with a method of Crespi, et al.(Analytical Biochemistry, 248, 188-190, 1997).

A 96 well plate was employed, and7-benzyloxy-4-(trifluoromethyl)coumarin (5×10⁻⁵ M) as a substrate, atest compound (4.9×10^(−85×10) ⁻⁵ M), and an enzyme (5×10⁻⁹ M) wereincubated in a total of 200 μl of a 200 mM phosphate buffer solution(pH=7.4) comprising 8.2 μM NADP+, 0.41 mM glucose-6-phosphate, 0.41 mMMgCl₂, and 0.4 Units/ml glucose-6-phosphate dehydrogenase, at 37° C. for30 minutes. Then, 0.5 M aqueous solution of2-amino-2-hydroxymethyl-1,3-propanediol containing 80% acetonitrile wasadded thereto to stop the reaction, and fluorescence intensity wasmeasured with a fluorescent plate reader (excited wavelength: 409 nm,fluorescent wavelength: 530 nm). Inhibition rate was calculated by thefollowing equation, and the concentration of the test compoundcorresponding to an inhibition rate of 50% (IC₅₀) was calculated. Theresults are described in the following Table 4.Inhibition Rate (%)=100−(C ₁ −B ₁)/(C ₀ −B ₁)×100

-   C₁: fluorescence intensity in the presence of a known concentration    of test compound, enzyme, and a substrate-   C₀: fluorescence intensity in the presence of an enzyme and a    substrate, in the absence of a test compound-   B₁: fluorescence intensity of a blank well    (5) Cytochrome P450 (2C9) Enzyme Inhibition Effects

The assay was carried out in accordance with a method of Crespi, et al.(Analytical Biochemistry, 248, 188-190, 1997).

A 96 well plate was employed, and 7-methoxy-4-(trifluoromethyl)coumarin(7.5×10⁻⁵ M) as a substrate, a test compound (4.9×10⁻⁸˜5×10⁻⁵M), and anenzyme (10⁻⁸ M) were incubated in a total of 200 μl of a 200 mMphosphate buffer solution (pH=7.4) comprising 8.2 μM NADP+, 0.41 mMglucose-6-phosphate, 0.41 mM MgCl₂, and 0.4 Units/ml glucose-6-phosphatedehydrogenase, at 37° C. for 45 minutes. Then, 0.5 M aqueous solution of2-amino-2-hydroxymethyl-1,3-propanediol containing 80% acetonitrile wasadded thereto to stop the reaction, and fluorescence intensity wasmeasured with a fluorescent plate reader (excited wavelength: 409 nm,fluorescent wavelength: 530 nm). Inhibition rate was calculated from theabove equation in (4), and the concentration of the test compoundcorresponding to an inhibition rate of 50% (IC₅₀) was calculated. Theresults are described in the following Table 4. TABLE 4 [CYP(3A4 and2C9) inhibition effects] IC₅₀ (μM) Compound CYP3A4 CYP2C9 Example 8 >2013 Example 190 16 6.5 Example 220 10 11 Control <0.091 <0.091

As shown in Table 4, the compound of the present invention showed verylow inhibition effects for the medicine metabolism enzymes CYP3A4 andCYP2C9. The control was the same as in Table 1.

A pharmaceutical composition of the present invention can be prepared bygenerally used methods using one or more kinds of the compound of thepresent invention and pharmaceutical carriers, fillers, and otheradditives generally used in the preparation of medicaments.

It may be administrated either by oral administration through tablets,pills, capsules, granules, powders, solutions, and the like, or byparenteral administration through injections such as intravenousinjection, intramuscular injection, and the like, or throughsuppositories, or pernasal, permucosal, or percutaneous preparations,and the like.

The solid composition for use in the oral administration according tothe present invention is used in the forms of tablets, powders,granules, and the like. In such a solid composition, one or more activesubstances are mixed with at least one inert diluent such as lactose,mannitol, glucose, hydroxypropylcellulose, microcrystalline cellulose,starch, polyvinyl pyrrolidone, metasilicate, or magnesium aluminate. Inthe usual way, the composition may contain additives other than theinert diluent, which include a lubricant such as magnesium stearate, adisintegrating agent such as calcium cellulose glycolate, a stabilizingagent such as lactose, and a solubilization-assisting agent such asglutamic acid or aspartic acid. As occasion demands, tablets or pillsmay be coated with a sugar coat or a film of gastrosoluble orenterosoluble substance such as sucrose, gelatin,hydroxypropylcellulose, hydroxypropylmethylcellulose phthalate, or thelike.

The liquid composition for oral administration includes pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, elixirs, and thelike, and it contains a generally used inert diluent such as purifiedwater or ethanol. In addition to the inert diluent, this composition mayalso contain auxiliary agents such as a moistening agent and asuspending agent, as well as a sweetener, a flavoring agent, anaromatic, and an antiseptic.

The injections for parenteral administration include aseptic aqueous ornon-aqueous solutions, suspensions, and emulsions. Examples of theaqueous solutions and suspensions include distilled water for injectionuse, and physiological saline. Examples of the non-aqueous solutions andsuspensions include plant oil such as propylene glycol, polyethyleneglycol, olive oil or the like, alcohol such as ethanol, polysorbate80-(trade name), and the like. Such a composition may further containauxiliary agents such as an antiseptic, a moistening agent, anemulsifying agent, a dispersing agent, a stabilizing agent (e.g.,lactose), and a solubilization-assisting agent (e.g., glutamic acid oraspartic acid. These compositions are sterilized, for example byfiltration through a bacteria retaining filter, blending of a germicide,or irradiation. Alternatively, they may be used by firstly making intosterile solid compositions and dissolving them in sterile water or asterile solvent for injection use, prior to their use.

In the case of oral administration, a daily dose is approximately0.0001˜50 mg/kg of body weight, preferably approximately 0.001˜10 mg/kg,and more preferably approximately 0.01˜1 mg/kg, and the daily dose isadministered once a day or by dividing it into 2 to 4 doses per day. Inthe case of intravenous administration, a daily dose is approximately0.0001˜1 mg/kg of body weight, preferably approximately 0.0001˜0.1mg/kg, and the daily dose is administered once a day or by dividing itinto plural doses per day. The dose is appropriately determined bytaking symptoms, age, the sex of the patient to be treated, and the likeinto consideration. Since the dose is varied depending on variousconditions, a smaller dose is sufficient in some cases.

BEST MODE FOR CARRYING OUT THE INVENTION

The following describes the invention more illustratively with referenceto examples, but the present invention is not limited to these examples.In this connection, novel materials are included in the startingmaterials to be used in the examples, and production methods of thestarting materials from known materials are described as referenceexamples.

REFERENCE EXAMPLE 1

20.85 g of methyl 2-chloro-4-fluorobenzoate were dissolved in 150 ml ofN-methylpyrrolidone, 30.68 g of potassium carbonate and 9.38 ml of3-methylpyrazole were added thereto, and the mixture was stirred at 120°C. for 3 hours. Additionally, thereto was added 1.79 ml of3-methylpyrazole, and the mixture was stirred at 120° C. for 3 hours.The reaction solution was cooled, mixed with water, and extracted withEtOAc. The organic layer was washed with water and brine, and then driedover magnesium sulfate. The solvent was evaporated, and then the residuewas purified by silica gel column chromatography (hexane-EtOAc (20:1))to obtain 9.25 g of methyl 2-chloro-4-(3-metyl-1H-pyrazol-1-yl)benzoate.

The compounds of Reference Examples 2-40 were synthesized in the samemanner as described in Reference Example 1.

REFERENCE EXAMPLE 41

2.0 g of methyl 4-amino-2-chlorobenzoate were dissolved in 10 ml ofacetic acid, 2.0 ml of 2,5-dimethoxytetrahydrofuran were added thereto,and the mixture was heated under reflux for 15 minutes. After coolingthe reaction solution, the solvent was evaporated. The obtained residuewas mixed with EtOAc and saturated NaHCO₃ aq. and extracted. The organiclayer was washed with brine, and dried over sodium sulfate anhydride.After evaporating the solvent, the residue was purified by silica gelcolumn chromatography (hexane-EtOAc (4:1)) to obtain 2.1 g of methyl2-chloro-4-(1H-pyrrol-1-yl)benzoate.

The compound of Reference Example 42 was synthesized in the same manneras described in Reference Example 41.

REFERENCE EXAMPLE 43

2.0 g of methyl 4-bromo-2-methylbenzoate were dissolved in 20 ml oftoluene, and 1.08 ml of pyrrolidine, 4.0 g of cesium carbonate, 200 mgof tris(dibenzylideneacetone)-dipalladium (0) and 200 mg of(R)-(+)-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl were added thereto,and then the mixture was heated under reflux for 6 hours. The reactionsolution was cooled, mixed with water and EtOAc, and extracted. Theorganic layer was washed with water and brine, and dried over anhydroussodium sulfate. After evaporating the solvent, the residue was purifiedby silica gel column chromatography (hexane-EtOAc (25:1)) to obtain0.784 g of methyl 2-methyl-4-pyrrolidin-1-ylbenzoate.

The compound of Reference Example 44 was synthesized in the same manneras described in Reference Example 43.

REFERENCE EXAMPLE 45

9.25 g of the compound of the Reference Example 1 were dissolved in 10ml of acetic acid and 10 ml of 6M HCl aq., and then the mixture washeated under reflux for 13 hours. The reaction solution was cooled, andthen poured into ice water, and the thus precipitated crystals werecollected by filtration to obtain 8.56 g of2-chloro-4-(3-methylpyrazol-1-yl) benzoic acid.

REFERENCE EXAMPLE 46

10.7 g of the compound of Reference Example 2 were dissolved in 60 ml ofMeOH and 20 ml of 5M NaOH aq., and the mixture was heated under refluxfor 2 hours. The reaction solution was cooled, and then neutralized with2M HCl aq., and the solvent was evaporated. To the obtained residue,water was added, and the thus precipitated crystals were collected byfiltration to obtain 10.17g of 2-chloro-4-pyrrolidin-1-ylbenzoic acid.

The compounds of Reference Examples 47-88 were synthesized in the samemanner as described in Reference Example 46.

The structures and physical data of the compounds of Reference Examplesare shown in Tables 5 to 8. Symbol meanings in the Tables are asfollows.

-   Rf: Reference Example number-   MS: Mass spectrometry data (FAB-MS(M+H)⁺unless otherwise noted, and    MM, MN, and ME respectively indicate FAB-MS(M)⁺, FAB-MS(M−H)⁺, and    EI-MS(M)⁺).

R^(b), R^(c), R^(d): substituent group in the general formula (Me:methyl, Et: ethyl, iPr: isopropyl, cPr: cyclopropyl, tBu: tert-butyl,Ph: phenyl, pra: pyrazolyl, pyrr: pyrrolinidyl, mor: morpholinyl, the:thienyl, imid: imidazolyl, bimid: benzoimidazolyl, pipe: piperidyl, di:di), The number before the substituent group indicates location ofsubstitution. Thus, for example, 3-Me-1-pra indicates3-methylpyrazol-1-yl, 3,3-diMe-1-pyrr indicates3,3-dimethylpyrrolidin-1-yl, and 3-(2-the)-1-pra indicates3-thiophene-2-ylpyrazol-1-yl. TABLE 5

Rf R^(b) R^(c) MS 1 Cl 3-Me-1-pra 251. 2 Cl 1-pyrr 240. 3 Cl 1-pra 237.4 Cl 4-mor ME:255. 5 Cl 3-Ph-1-pra 313. 6 Cl 4-Br-1-pra 315,317. 7 Cl3-(2-the)-1-pra 319. 8 Cl indazol-1-yl 287. 9 Cl 3,5-diMe-1-pra 265. 10Cl 2-Me-imid 251. 11 Cl 1-bimid 287. 12 Cl 5-Me-1-pra 251. 13 Cl2-Me-1-pyrr 254. 14 Cl 3-(R)—Me-1-pyrr 254. 15 Cl 3-(S)—Me-1-pyrr 254.16 Cl 3,3-diMe-1-pyrr MM:267. 17 Cl 3-F-1-pyrr 258. 18 Cl 3-Ph-1-pyrr316. 19 Cl 3-Me-3-Et-1-pyrr 282. 20 Cl 3,5-diMe-1-pipe 282. 21 Cl3-Me-1-pipe 268. 22 Cl 3-Et-1-pra 265. 23 Cl 3-iPr-1-pra 279. 24 Cl3-cPr-1-pra 277. 25 CF₃ 1-pyrr 274. 26 CF₃ 3-Me-1-pra 285. 27 CF₃3-(R)—Me-1-pyrr 288. 28 CF₃ 3-(S)—Me-1-pyrr 288. 29 CF₃ 3,4-diMe-1-pyrr302. 30 CF₃ 3,3-diMe-1-pyrr MM:301. 31 CF₃ 2,5-dihydropyrrol-1-yl 272.32 CF₃ 3-iPr-1-pra 313. 33 CF₃ 3-F₃C-1-pra 339. 34 CF₃ 3,5-diMe-1-pra299. 35 CF₃ 4-Me-1-pra 285. 36 CF₃ 3-tBu-1-pra 327. 37 CF₃ 5-Me-1-pra285. 39 Cl 1-pipe ME:253. 40 Cl azepin-1-yl ME:267. 41 Cl pyrrol-1-yl236. 42 Cl 2,5-diMe-pyrrol-1-yl MM:263. 43 Me 1-pyrr 220.

TABLE 6

Rf R^(c) R^(d) MS 38 3-Me-1-pra F 269. 44 H 1-pyrr 240.

TABLE 7

Rf R^(b) R^(c) MS 45 Cl 3-Me-1-pra MN:235. 46 Cl 1-pyrr 226. 47 Cl 1-pra223. 48 Cl 4-mor MN:241. 49 Cl 3-Ph-1-pra MN:297. 50 Cl 4-Br-1-praMN:299,301. 51 Cl 3-(2-the)-1-pra MN:303. 52 Cl indazol-1-yl MN:271. 53Cl 3,5-diMe-1-pra MN:249. 54 Cl pyrrol-1-yl MN:220. 55 Cl 2-Me-1-imid237. 56 Cl 1-bimid 273. 57 Cl 5-Me-1-pra MN:235. 58 Cl 2-Me-1-pyrr 240.59 Cl 3-(R)—Me-1-pyrr 240. 60 Cl 3-(S)—Me-1-pyrr 240. 61 Cl3,3-diMe-1-pyrr 254. 62 Cl 3-F-1-pyrr 244. 63 Cl 3-Ph-1-pyrr MN:300. 64Cl 3-Me-3-Et-1-pyrr 268. 65 Cl 3,5-diMe-1-pipe MN:266. 66 Cl 3-Me-1-pipeMN:252. 67 Cl 3-Et-1-pra 251. 68 Cl 3-iPr-1-pra 265. 69 Cl 3-cPr-1-pra263. 70 Cl 2,5-diMe-pyrrol-1-yl MN;248. 71 CF₃ 1-pyrr 258. 72 CF₃3-Me-1-pra 271. 73 CF₃ 3-(R)—Me-1-pyrr 274. 74 CF₃ 3-(S)—Me-1-pyrrMN;272. 75 CF₃ 3,4-diMe-1-pyrr 288. 76 CF₃ 3,3-diMe-1-pyrr 288. 77 CF₃2,5-dihydropyrrol-1-yl 258. 78 CF₃ 3-iPr-1-pra 299. 79 CF₃ 3-F₃C-1-praMN:323. 80 CF₃ 3,5-diMe-1-pra 285. 81 CF₃ 4-Me-1-pra 271. 82 CF₃3-tBu-1-pra 313. 83 CF₃ 5-Me-1-pra 271. 84 Me 1-pyrr 206. 85 Cl 1-pipeMN:238. 86 Cl azepin-1-yl MN:252.

TABLE 8

Rf R^(c) R^(d) MS 87 3-Me-1-pra F 255. 88 H 1-pyrr 226.

REFERENCE EXAMPLE 89

8.0 g of methyl(2Z)-(4,4-difluoro-1,2,3,4-tetrahydro-5H-1benzazepin-5-ylidene)acetatewere dissolved in 20 ml of MeOH and 20 ml of THF. 45 ml of 1M NaOH aq.were added thereto, and the mixture was stirred at room temperature for15 hours. The reaction solution was concentrated under reduced pressure,and the residue was neutralized with 1M HCl aq. The reaction solutionwas mixed with chloroform and extracted. The organic layer was washedwith brine, dried over sodium sulfate, and the solvent was evaporated toobtain 4.57 g of carboxylic acid intermediate. 4.57 g of the carboxylicacid intermediate were dissolved in 45 ml of DMF. 2.22 ml of 2-picolylamine, 3.6 g of 1-hydroxybenzoimidazol (HOBt), and 5.6 g of1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (EDCI.HCl)were added thereto, and the mixture was stirred at room temperature for18 hours. The reaction solution was mixed with water and EtOAc andextracted therewith. The organic layer was washed with brine, and driedover sodium sulfate anhydride. After evaporation of the solvent, theresidue was purified by silica gel column chromatography(chloroform-MeOH (25:1)) to obtain 6.849 g of(2Z)-2-(4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene)-N-(pyridine-2-ylmethyl)acetamide.FAB-MS; 330. ([M+H]⁺)

REFERENCE EXAMPLE 90

To a solution of 1.37 g of the compound of Example 6, 0.45 g of HOBt,and 0.63 g of EDCI HCl in 15 ml of DMF, 0.46 g of sarcosinic methylesterhydrochloride and 0.47g of triethylamine were added, and the mixture wasstirred at room temperature overnight. The reaction solution was mixedwith NaHCO₃ aq. and EtOAc and extracted. The organic layer was washedwith water and brine, and dried over anhydrous magnesium sulfate. Afterevaporation of the solvent, the obtained ester intermediate wasdissolved in 20 ml of MeOH, 5 ml of 1M NaOH aq. was added thereto, andthe mixture was stirred at room temperature for 1 hour. To the crudeproduct obtained by the evaporation of the solvent, 1M HCl aq. wasadded, and the thus precipitated white crystals were collected byfiltration, washed with water, and dried under reduced pressure toobtain 1.43 g of[((2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazpine-5-ylidene}acetyl(methyl)amino)aceticacid.

FAB-MS; 529. ([M+H]⁺)

EXAMPLE 1

To a suspension of 21.0 g of2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoic acid in 200 ml of1,2-dichloroethane, 15 ml of thionyl chloride and 3 drops of DMF wereadded at room temperature, and the mixture was stirred at 70° C. for 2hours. The reaction solution was cooled to room temperature, the solventwas evaporated, and the residue was dried to obtain acid chloride form.22.5 g of methyl(2Z)-(4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene)acetatewere added thereto, 200 ml of pyridine was added thereto under icecooling, and the mixture was stirred at room temperature for 20 hours.After completion of the reaction, the solvent was evaporated, and theresidue was mixed with diluted hydrochloric acid water and EtOAc andextracted. The organic layer was washed with brine, and dried overanhydrous magnesium sulfate. After evaporation of the solvent, theresidue was purified by silica gel column chromatography (hexane-EtOAc(9:1˜4:1)) to obtain 38.0 g of methyl(2Z)-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetate.

EXAMPLE 2

To a solution of 3.0 g of 4-bromo-2-methylbenzoic acid in 20 ml of THFand 1 drop of DMF, 1.9 ml of oxalyl chloride was added under icecooling, and the mixture was stirred at room temperature for 2 hours.The reaction solution was concentrated, and the residue was mixed with 3ml of toluene and concentrated again. The obtained residue was mixedwith 20 ml of pyridine and 3.5 g of methyl(2Z)-(4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene)acetateand the mixture was stirred at room temperature for 12 hours. Thereaction mixture was concentrated, then to the mixture was addedchloroform and 1M aqueous NaOH and was extracted. The organic layer waswashed with water and brine, and dried over anhydrous sodium sulfate.After evaporation of the solvent, the residue was purified by silica gelcolumn chromatography (hexane-EtOAc (6:1)) to obtain 5.94 g of methyl(2Z)-[1-(4-bromo-2-methylbenzoyl)-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene] acetate.

EXAMPLE 3

To a solution of 4.62 g of 2-(trifluoromethyl)benzoic acid in 30 ml ofsulfuric acid, 3.48 g of 1,3-dibromo-5,5-dimethylhydantoin were added.The mixture was stirred at room temperature for 15 hours, and then addedto ice water dropwise. 5M NaOH aq. were added to the reaction solutionto control pH of the solution to 12, and then the reaction solution wasextracted with chloroform. To the aqueous layer, concentratedhydrochloric acid was added to control the pH of the solution to 1, andthen the reaction solution was extracted with chloroform. The organiclayer was washed with water and brine, and dried over anhydrous sodiumsulfate. After evaporation of the solvent, 20 ml of THF and 1 drop ofDMF were added to the residue, and 2.5 ml of oxalyl chloride were addedthereto under ice cooling, and then the mixture was stirred at roomtemperature for 2 hours. The reaction solution was concentrated underreduced pressure, and the residue was mixed with 10 ml of toluene andconcentrated again. To the obtained residue, 20 ml of pyridine and 6.2 gof methyl (2Z)-(4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene)acetate were added, and themixture was stirred at room temperature for 12 hours. The reactionsolution was concentrated, and the residue was mixed with chloroform and1M HCl aq. and extracted. The organic layer was washed with water andbrine, and dried over anhydrous sodium sulfate. After evaporation of thesolvent, the residue was purified by silica gel column chromatography(hexane-EtOAc(6:1)). And, the residue obtained by concentration underreduced pressure was crystallized from EtOH to obtain 3.66 g of methyl(2Z)-{1-[4-bromo-2-(trifluoromethyl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetate.

EXAMPLE 4

To a solution of 2.0 g of the compound of Example 2 in 30 ml of toluene,22.35 g of tert-butyl hydrazine carboxylate, 1.43 g of cesium carbonate,400 mg of tris(dibenzylideneacetone)dipalladium (0), and 740 mg of1,1′-bis(diphenylphosphine)ferrocene were added, and the mixture wasstirred at 100° C. for 4 hours. After cooling the reaction solution,insoluble matter was filtered, and EtOAc and 10% citric acid aqueoussolution were added to the filtrate to extract it. The organic layer waswashed with water and brine, and dried over anhydrous sodium sulfateanhydride. After evaporation of the solvent, the residue was purified bysilica gel column chromatography (hexane-EtOAc (2:1)) to obtain 1.0 g oftert-butyl1-(4-{[(5Z)-4,4-difluoro-5-(2-methyl-2-oxoethylidene)-2,3,4,5-tetrahydro-1H-1-benzazepin-1-yl]carbonyl}-3-methylphenyl)hydrazinecarboxylate.

EXAMPLE 5

To a solution of 1.0 g of the compound of Example 4 in 10 ml of EtOAc,10 ml of 4M HCl-EtOAc were added, and the mixture was stirred at roomtemperature for 4 hours. The reaction solution was concentrated underreduced pressure, and the residue was mixed with saturated NaHCO₃ aq.and chloroform and extracted. The organic layer was washed with waterand brine, and dried over anhydrous sodium sulfate. After evaporation ofthe solvent, 40 ml of MeOH and 275 mg of acetylacetaldehydedimethylacetal were added to the residue, and the mixture was heatedunder reflux for 1.5 hours. To the reaction solution, 3 drops of conc.hydrochloric acid were added, and the mixture was heated under refluxfor 30 minutes again. The reaction solution was cooled, and thenconcentrated under reduced pressure. The residue was mixed withsaturated sodium hydrogen carbonate aqueous solution and chloroform andextracted. The organic layer was washed with water and brine, and driedover anhydrous sodium sulfate. After evaporation of the solvent, theresidue was purified by silica gel column chromatography (hexane-EtOAc(4:1)) to obtain 561 mg of methyl(2Z)-{4,4-difluoro-1-[2-methyl-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetate.

EXAMPLE 6

38.0 g of the compound of Example 1 were dissolved in 120 ml of MeOH and120 ml of THF, 100 ml of 1M NaOH aq. was added at room temperature, andthe mixture was stirred for 10 hours. Approximately 200 ml of thesolvent were evaporated under reduced pressure, 0.5M HCl aq. were addedto the residue under ice cooling, and the mixture was stirred for 1hour. Thus formed white precipitations were filtered and dried to obtain36.5 g of(2Z)-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-1H-1-benzazepin-5-ylidene}aceticacid in the form of powder.

EXAMPLE 7

To a solution of 229 mg of the compound of Example 6, 71 mg of HOBt and101 mg of EDCI HCl in 3 ml of DMF, 35 mg of thiophen-2-ylmethylaminewere added, and the mixture was stirred at room temperature overnight.The reaction solution was mixed with saturated sodium bicarbonateaqueous solution and chloroform, and extracted. The organic layer wasdried over anhydrous magnesium sulfate, and the solvent was evaporated.Then, the residue was purified by silica gel column chromatography(chloroform-MeOH (30:1)). The residue obtained by concentration underreduced pressure was crystallized from a 2-propanol-diisopropyl ethersolvent mixture to obtain 61 mg of(2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl]benzoyl}-4,4-difluoro-1,2,3,4,-tetrahydro-5H-1-benzazepin-5-ylidene}-N-(thiophen-2-ylmethyl)acetamide.

EXAMPLE 8

210 mg of the compound of Example 6 were dissolved in 20 ml ofdichloroethane, 2 ml of thionyl chloride were added, and the mixture wasstirred at room temperature for 30 minutes. The reaction solution wasconcentrated under reduced pressure, and the residue was mixed withtoluene and concentrated again. The obtained acid chloride form weredissolved in 30 ml of acetonitrile, and added dropwise to 30 ml ofammonia water at room temperature. After stirring at room temperaturefor 12 hours, the formed white precipitations were filtered and dried toobtain 259 mg of(2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-benzazepine}acetamidein the form of powder.

EXAMPLE 9

915 mg of the compound of Example 14 were dissolved in 20 ml of MeOH, 3ml of 1M NaOH aq. were added, and the mixture was stirred at roomtemperature for 15.5 hours. The solvent was evaporated under reducedpressure, and then the residue was acidified with 1M HCl aq. andextracted with chloroform. The organic layer was washed with water andbrine, and dried over anhydrous sodium sulfate. After evaporation of thesolvent, the obtained carboxylic acid intermediate was dissolved in 10ml of DMF, 0.24 ml of 2-picolyl amine, 0.39 g of HOBt and 0.61 g of EDCIHCl were added thereto, and the mixture was stirred at room temperaturefor 84 hours. The reaction solution was mixed with water and EtOAc, andextracted. The organic layer was washed with brine, and dried overanhydrous sodium sulfate. After evaporation of the solvent, the residuewas purified by silica gel column chromatography (chloroform-MeOH(35:1)). The residue obtained by concentration under reduced pressurewas dissolved in EtOAc, 0.4 ml of 4M HCl-EtOAc solution was addedthereto, and the solvent was evaporated under reduced pressure. Theobtained residue was crystallized from EtOH to obtain 0.456 g of(2Z)-2-[1-(2-chloro-4-pyrrolidin-1-ylbenzoyl)-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene]-N-(pyridin-2-ylmethyl)acetamidehydrochloride.

EXAMPLE 10

0.25 g of the compound of Example 93 were dissolved in 10 ml of MeOH, 10ml of 1M NaOH were added, and the mixture was stirred at roomtemperature for 16 hours. The reaction solution was neutralized with 1MHCl aq., and extracted with chloroform. The organic layer was washedwith water and brine, and dried over anhydrous magnesium sulfate. Afterevaporation of the solvent, the residue was crystallized from anEtOAc-hexane solvent mixture to obtain 116 mg of[((2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetyl)amino]acetic acid.

EXAMPLE 11

To a solution of 258 mg of the compound of Example 10, 71 mg of HOBt and101 mg of EDCI.HC in 5 ml of THF, and 0.5 ml of 2.0 M methylamine-THFsolution were added, and the mixture was stirred at room temperatureovernight. The reaction solution was mixed with saturated NaHCO₃ aq. andextracted with chloroform. The organic layer was dried over anhydrousmagnesium sulfate. The crude product obtained by evaporation of thesolvent was purified by silica gel column chromatography(chloroform-MeOH (30:1)). The residue obtained by concentration underreduced pressure was crystallized from a 2-propanol-hexane solventmixture to obtain 51 mg of(2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}-N-[2-(methylamino)-2-oxoethyl]acetamide.

EXAMPLE 12

To a solution of 265 mg of the compound of Reference Example 90 in 5 mlof THF, 82 mg of 1,1′-carbonylbis-1H-imidazole were added, and themixture was stirred at room temperature for 0.1 hour. Then, ammoniawater was added to the reaction solution, and the mixture was stirred atroom temperature for 22 hours. The reaction solution was mixed withwater and EtOAc, and extracted therewith. The organic layer was washedwith water and brine, and dried over anhydrous magnesium sulfate. Thecrude product obtained by evaporation of the solvent was purified bysilica gel column chromatography (chloroform-MeOH(100:1)). The residueobtained by concentration under reduced pressure was crystallized from a2-propnaol-diisopropyl ether solvent mixture to obtain 41 mg of(2Z)-N-[2-amino-2-oxoethyl]-N-methyl-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetamide.

EXAMPLE 13

To a solution of 0.35 g of the compound of Reference Example 85 in 10 mlof THF and 1 drop of DMF, 0.22 ml of thionylchloride were added underice cooling, and the mixture was stirred at room temperature for 2.5hours. The reaction solution was concentrated under reduced pressure,and the residue was mixed with 3 ml of toluene and concentrated again.The obtained residue was dissolved in 20 ml of acetonitrile, 0.4 g ofthe compound of Reference Example 89 and 0.4 ml of pyridine were added,and the mixture was stirred at 80° C. for 17 hours. After cooling thereaction solution, the solvent was evaporated, and the residue was mixedwith chloroform and 10% citric acid aqueous solution, and extractedtherewith. The organic layer was washed with saturated sodiumbicarbonate aqueous solution, water, and brine, and the dried overanhydrous sodium sulfate. After evaporation of the solvent, the residuewas purified by silica gel column chromatography(chloroform-MeOH-ammonia water (25:0:0.1)). The residue obtained byconcentration under reduced pressure was dissolved in EtOAc, 0.18 ml of4M HCl-EtOAc solution was added thereto, and the solvent was evaporatedunder reduced pressure. The obtained residue was crystallized from EtOHto obtain 0.176 g of(2Z)-2-[1-(2-chloro-4-piperidin-1-ylbenzoyl)-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene]-N-(pyridine-2-ylmethyl)acetamide hydrochloride.

The structures and physicochemical data of the compounds of Examples areshown in Tables 9. Additionally, the structures and physicochemical dataof the compounds obtained by the same production method are also shownin Tables 9 to 16. The symbols in the Tables have the followingmeanings.

Ex: Number of Example

-   Salt: salt (HCl: hydrochloride, inorganic material: free form)-   Syn: synthesis method (The number indicates the number of Example of    which method is applied)

R^(A), R^(B), R^(C), R^(D), R^(1A): substituent group in the generalformula (npen: normal pentyl, cHex: cyclohexyl, Ac: acetyl, Ms: mesyl,Boc: tert-butyloxycarbony, py: pyridyl, fur:furyl, thia: thiazolyl,bthia: benzothiazolyl. Thus, as examples, —NH₂CH₂-(2-py) indicatespyridine-2-ylmethylamino, —NH₂CH₂-(4-HO-3-MeO-Ph) indicates4-hydroxy-3-methoxybenzylamino, and 2-HOCH₂-1-pipe indicates2-hydroxymethylpiperidin-1-yl.) TABLE 9

Ex(Salt) R^(A) R^(B) R^(C) MS Syn  1 —OMe Cl 3-Me-1-pra 472. 1  2 —OMeMe —Br 452. 2  3 —OMe CF₃ —Br 504. 3  4 —OMe Me —N(Boc)NH₂ 502. 4  5—OMe Me 3-Me-1-pra 452. 5  6 —OH Cl 3-Me-1-pra 458. 6  7 —NHCH₂-(2-the)Cl 3-Me-1-pra 553. 7  8 —NH₂ Cl 3-Me-1-pra 457. 8  9(HCl) —NHCH₂-(2-py)Cl 1-pyrr 538. 9 10 —NHCH₂CO₂H Cl 3-Me-1-pra 515. 10 11 —NHCH₂CONHMe Cl3-Me-1-pra 528. 11 12 —N(Me)CH₂CONH₂ Cl 3-Me-1-pra 528. 12 13(HCl)—NHCH₂-(2-py) Cl 1-pipe 551. 13

TABLE 10

Ex(Salt) R^(B) R^(C) MS Syn 14 Cl 1-pyrr 461. 1 15 Cl 2-Me-1-pyrr 475. 116 Cl 3-Me-1-pyrr 475. 1 17 Cl 3-(R)—Me-1-pyrr MM;474. 1 18 Cl3-(S)—Me-1-pyrr 475. 1 19 Cl 3,3-diMe-1-pyrr 489. 1 20 Cl3-Me-3-Et-1-pyrr 503. 1 21 Cl 3-F-1-pyrr 479. 1 22 Cl 3-Ph-1-pyrr 538. 123 CF₃ 1-pyrr 495. 1 24 CF₃ 3-(R)—Me-1-pyrr 509. 1 25 CF₃3-(S)—Me-1-pyrr 509. 1 26 CF₃ 3,4-diMe-1-pyrr 523. 1 27 CF₃3,3-diMe-pyrr 523. 1 28 Me 1-pyrr 441. 1 29 Cl 1-pra 458. 1 30 Cl5-Me-1-pra 472. 1 31 Cl 3-Et-1-pra 486. 1 32 Cl 3-iPr-1-pra 500. 1 33 Cl3-cPr-1-pra 498. 1 34 Cl 3,5-diMe-1-pra 486. 1 35 Cl 4-Br-1-pra 536,538.1 36 Cl 3-Ph-1-pra 534. 1 37 Cl 3-(2-the)-1-pra 540. 1 38 CF₃ 3-Me-1-pra506. 1 39 CF₃ 3-Me-1-pra 506. 5 40 CF₃ 4-Me-1-pra 506. 1 41 CF₃5-Me-1-pra 506. 1 42 CF₃ 3-iPr-1-pra 534. 1 43 CF₃ 3-F₃C-1-pra 560. 1 44CF₃ 3-tBu-1-pra 548. 1 45 CF₃ 3,5-diMe-1-pra 520. 1 46 Cl 3-Me-1-pipe565. 1 47 Cl 3,5-diMe-1-pipe 579. 1 48 Cl 4-mor 477. 1 49 Cl pyrrol-1-yl457. 1 50 Cl 2,5-diMe-pyrrol-1-yl 485. 1 51 CF₃ 2,5-dihydro- 493. 11H-pyrrol-1-yl 52 Cl 2-Me-imidazol-1-yl 472. 1 53 Cl 1-bimid 508. 1 54Cl indazol-1-yl 508. 1 55 CF₃ —N(Boc)NH₂ 556. 4

TABLE 11

Ex (Salt) R^(A) R^(B) MS Syn  56 3-HO-1-pyrr Cl 527. 7  57 3-HO-1-pipeCl 541. 7  58 3-H₂NOC-1-pipe Cl 568. 7  59 4-H₂NOC-1-pipe Cl 568. 7  602-HOCH₂-1-pipe Cl 555. 7  61 3-HOCH₂-1-pipe Cl 555. 7  62—NH-(2-HO-cHex) Cl 555. 7  63 —NHPh Cl 533. 7  64 —NH-(2-HO—Ph) Cl 549.7  65 —NH-(3-HO—Ph) Cl 549. 7  66 —NH-(4-HO—Ph) Cl 549. 7  67—NH-(3-Ac—Ph) Cl 575. 7  68 —NH-(3-HO₂C—Ph) Cl 577. 7  69—NH-(3-MeO₂C—Ph) Cl 591. 7  70 —NH-(2-H₂NOC—Ph) Cl 576. 7  71—NH-(3-H₂NOC—Ph) Cl 576. 7  72 —NH-(4-H₂NOC—Ph) Cl 576. 7  73—NH-(3-MeNHCO—Ph) Cl 590. 7  74 —NH-(3-Me—Ph) Cl 547. 7  75—NH-(2-HOCH₂—Ph) Cl 563. 7  76 —NH-(3-HOCH₂—Ph) Cl 563. 7  77—NH-(4-HOCH₂—Ph) Cl 563. 7  78 —NH-(3-HO(CH₂)₂—Ph) Cl 577. 7  79—NH-(3-MeCH(OH)—Ph) Cl 577. 7  80 —NH-(2-HOCH₂CH(OH)—Ph) Cl 593. 7  81—NH-(4-HOCH₂CH(OH)—Ph) Cl 593. 7  82 —NH-(3-MeOCH₂—Ph) Cl 577. 7  83—NH-(3-H₂NOCCH₂—Ph) Cl 590. 7  84 —NH-(3-H₂NOC(CH₂)₂—Ph) Cl 604. 7  85—NH-(3-H₂NOC—(E)—CH═CH—Ph) Cl 602. 7  86 —NH-(3-F—Ph) Cl 551. 7  87—NH-(3-Ms—Ph) Cl 611. 7  88 —NH-(3-AcNH—Ph) Cl 590. 7  89 —NH-(3-the) Cl539. 7  90

Cl 540. 7  91

Cl 541. 7  92

Cl 557. 7  93 —NHCH₂CO₂Me Cl 529. 7  94 —NHCH₂CONH₂ Cl 514. 7  95—NHCH₂Ph Cl 547. 7  96 —NHCH₂-(4-HO—Ph) Cl 563. 7  97 —NHCH₂-(3-HO—Ph)Cl 563. 7  98 —NHCH₂-(2-HO—Ph) Cl 563. 7  99 —NHCH₂-(3,4-diHO—Ph) Cl579. 7 100 —NHCH₂-(4-MeO—Ph) Cl 577. 7 101 —NHCH₂-(3,4-diMeO—Ph) Cl 607.7 102 —NHCH₂-(4-HO-3-MeO—Ph) Cl 593. 7 103 —NHCH₂-(4-HO₂C—Ph) Cl 591. 7104 —NHCH₂-(4-MeO₂C—Ph) Cl 605. 7 105 —NHCH₂-(4-H₂NOC—Ph) Cl 590. 7 106—NHCH₂-(3-H₂NOC—Ph) Cl 590. 7 107 —NHCH₂-(3-HOCH₂—Ph) Cl 577. 7 108—NHCH₂-(4-F—Ph) Cl 565. 7 109 —NHCH₂-(4-H₂NO₂S—Ph) Cl 626. 7 110—NHCH₂-(2-py) Cl 548. 7 (HCl) 111 —NHCH₂-(6-HO-2-py) Cl 564. 7 112—NHCH₂-(5-MeO-2-py) Cl 578. 7 113 —NHCH₂-(6-MeO-2-py) Cl 578. 7 (HCl)114 —NHCH₂-(6-iPrO-2-py) Cl 606. 7 115 —NHCH₂-(6-H₂NOC-2-py) Cl 591. 7116 —NHCH₂-(6-Me₂NOC-2-py) Cl 619. 7 117 —NHCH₂-(6-cyano-2-py) Cl 573. 7118 —NHCH₂-(5-Me-2-py) Cl 562. 7 119 —NHCH₂-(6-Me-2-py) Cl 562. 7 (HCl)120 —NHCH₂-(6-HOCH₂-2-py) Cl 578. 7 (HCl) 121 —NHCH₂-(6-H₂N-2-Me-3-py)Cl 577. 7 (HCl) 122 —NHCH₂-(6-H₂N-2-py) Cl 563. 7 (HCl) 123—NHCH₂-(6-Me₂N-2-py) Cl 591. 7 124 —NHCH₂-(6-F-2-py) Cl 566. 7 125—NHCH₂-(6-Cl-2-py) Cl 582. 7 126 —NHCH₂-(3-py) Cl 548. 7 (HCl) 127—NHCH₂-(3-the) Cl 553. 7 128 —NHCH₂-(2-fur) Cl 537. 7 129—NHCH₂-(2-thia) Cl 554. 7 130 —NHCH₂-(4-thia) Cl 554. 7 131—NHCH₂-(pyrazol-2-yl) Cl 549. 7 (HCl) 132 —NHCH₂-(pyridazin-3-yl) Cl549. 7 133 —NHCH₂-(pyrimidin-4-yl) Cl 549. 7 134 —NHCH₂-(pyridazin-4-yl)Cl 549. 7 135 —NHCH₂-(2-bimid) Cl 587. 7 (HCl) 136 —NHCH₂-(1-Me-2-bimid)Cl 601. 7 (HCl) 137 —NHCH₂-(2-bthia) Cl 604. 7 138 —NHCH(CONH₂)₂ Cl 557.7 139 —NH(CH₂)₂OH Cl 501. 7 140 —(R)—NHCH(Me)CH₂OH Cl 515. 7 141—(S)—NHCH(Me)CH₂OH Cl 515. 7 142 —(R)—NHCH₂CH(Me)OH Cl 515. 7 143—(S)—NHCH₂CH(Me)OH Cl 515. 7 144 —NHC(Me)₂CH₂OH Cl 529. 7 145—NHCH₂C(Me)₂OH Cl 529. 7 146 —NH(CH₂)₂OMe Cl 515. 7 147 —NH(CH₂)₂CONH₂Cl 528. 7 148 —NHCH(CO₂Me)CH₂OH Cl 559. 7 149 —NHCH(CONH₂)CH₂OH Cl 544.7 150 —NHCH(Ph)CH₂OH Cl 577. 7 151 —NH(CH₂)₃OH Cl 515. 7 152—NHCH₂CH(OH)CH₂OH Cl 531. 7 153 —NHCH(CH₂OH)₂ Cl 531. 7 154 —NH(CH₂)₄OHCl 529. 7 155 —NHnPen Cl 527. 7 156 —NMe₂ Cl 485. 7 157 —N(Me)(CH₂)₂OHCl 515. 7 158 —N((CH₂)₂OH)₂ Cl 545. 7 159 —N(CH₂CONH₂)((CH₂)₂OH) Cl 558.7 160 —N(CH₂-2-py)((CH₂)₂OH) Cl 592. 7 161 —N(CH₂CONH₂)₂ Cl 571. 7 162—NH₂ CF₃ 491. 9(8) 163 —NH(CH₂)₂OH CF₃ 535. 9 164 —NHCH₂CONH₂ CF₃ 548. 9165 —NHCH₂-(2-py) CF₃ 582. 9 (HCl) 166 —NHCH₂CONH₂ Me 494. 9 167 —NH₂ Me437. 9(8)

TABLE 12

Ex(Salt) R^(B) R^(C) MS Syn 168 Cl 1-pyrr 446. 9(8) 169 Cl3,3-diMe-1-pyrr 474. 9(8) 170 Cl 3-F-1-pyrr 464. 9(8) 171 Cl 3-Ph-1-pyrr522. 9(8) 172 Cl 3-Me-3-Et-1-pyrr 488. 9(8) 173 Cl 3-(S)—Me-1-pyrr 460.9(8) 174 Cl 3-(R)—Me-1-pyrr 460. 9(8) 175 CF₃ 1-pyrr 480. 9(8) 176 CF₃3-(R)—Me-1-pyrr 494. 9(8) 177 CF₃ 3-(S)—Me-1-pyrr 494. 9(8) 178 CF₃3,3-diMe-1-pyrr 508. 9(8) 179 CF₃ 3,4-diMe-1-pyrr 508. 9(8) 180 CF₃4-Me-1-pra 491. 9(8) 181 CF₃ 5-Me-1-pra 491. 9(8) 182 CF₃ 3-iPr-1-pra519. 9(8) 183 CF₃ 3-tBu-1-pra 533. 9(8) 184 CF₃ 3-F₃C-1-pra 545. 9(8)185 CF₃ 3,5-diMe-1-pra 505. 9(8)

TABLE 13

Ex(Salt) R^(B) R^(C) MS Syn 186(HCl) Cl 2-Me-1-pyrr 551. 9 187(HCl) Cl3-Me-1-pyrr 551. 9 188(HCl) Cl 3,3-diMe-1-pyrr 565. 9 189(HCl) Cl3-F-1-pyrr 555. 9 190(HCl) Cl 1-pra 534. 9 191(HCl) Cl 5-Me-1-pra 547. 9192(HCl) Cl 3-Et-1-pra 562. 9 193(HCl) Cl 3-iPr-1-pra 576. 9 194(HCl) Cl3-cPr-1-pra 574. 9 195(HCl) Cl 3,5-diMe-1-pra 562. 9 196 Cl 4-Br-1-pra612,614. 9 197 Cl 3-Ph-1-pra 610. 9 198 Cl 3-(2-the)-1-pra 616. 9199(HCl) Cl 3-Me-1-pipe 565. 9 200(HCl) Cl 3,5-diMe-1-pipe 579. 9201(HCl) Cl 4-mor 553. 9 202(HCl) Cl azepin-1-yl 565. 13 203(HCl) Clpyrrol-1-yl 533. 9 204(HCl) Cl 2,5-diMe-pyrrol-1-yl 561. 9 205 Cl2-Me-1-imid 548. 9 206(HCl) Cl 1-bimid 584. 9 207(HCl) Cl indazol-1-yl584. 9 208(HCl) CF₃ 1-pyrr 571. 9 209(HCl) Me 1-pyrr 517. 9

TABLE 14

Ex (Salt) R^(A) R^(B) R^(C) MS Syn 210 —NH(CH₂)₂OH Cl 1-pyrr 490. 9 211—NH(CH₂)₂OH Cl 3-(R)—Me-1-pyrr 504. 9 212 —NH(CH₂)₂OH Cl 3-(S)—Me-1-pyrr504. 9 213 —NH(CH₂)₂OH Cl 3,3-diMe-1-pyrr 518. 9 214 —NH(CH₂)₂OH CF₃1-pyrr 524. 9 215 —NH(CH₂)₂OH CF₃ 3-(R)—Me-1-pyrr 538. 9 216 —NH(CH₂)₂OHCF₃ 3-(S)—Me-1-pyrr 538. 9 217 —NH(CH₂)₂OH CF₃ 3,3-diMe-1-pyrr 552. 9218 —NH(CH₂)₂OH CF₃ 3,4-diMe-1-pyrr 552. 9 219 —NH(CH₂)₂OH CF₃4-Me-1-pra 535. 9 220 —NHCH₂CONH₂ Cl 1-pyrr 503. 9 221 —NHCH₂CONH₂ Cl3-(R)—Me-1-pyrr 517. 9 222 —NHCH₂CONH₂ Cl 3-(S)—Me-1-pyrr 517. 9 223—NHCH₂CONH₂ Cl 3,3-diMe-1-pyrr 531. 9 224 —NHCH₂CONH₂ Cl 3-Ph-1-pyrr579. 9 225 —NHCH₂CONH₂ Cl 3-Me-3-Et-1-pyrr 545. 9 226 —NHCH₂CONH₂ CF₃1-pyrr 537. 9 227 —NHCH₂CONH₂ CF₃ 3-(R)—Me-1-pyrr 551. 9 228 —NHCH₂CONH₂CF₃ 3-(S)—Me-1-pyrr 551. 9 229 —NHCH₂CONH₂ CF₃ 3,3-diMe-1-pyrr 565. 9230 —NHCH₂CONH₂ CF₃ 3,4-diMe-1-pyrr 565. 9 231 —NHCH₂CONH₂ CF₃3-F₃C-1-pra 602. 9 232 —NHCH₂CONH₂ CF₃ 4-Me-1-pra 548. 9 233 —NHCH₂CONH₂CF₃ 3-tBu-1-pra 590. 9 234 —NHCH₂CONH₂ CF₃ 2,5-dihydropyrrol-1-yl 535. 9

TABLE 15

Ex(Salt) R^(A) R^(B) R^(C) R^(D) MS Syn 235 OMe Cl H 1-pyrr 461. 1 236OMe Cl 3-Me-1-pra F 490. 1 237(HCl) —NHCH₂-(2-py) Cl H 1-pyrr 537. 9 238—NH₂ Cl 3-Me-1-pra F 474. 9(8)

TABLE 16

Ex(Salt) R^(1A) R^(B) R^(C) MS Syn 239 —NMe₂ Cl 3-Me-1-pra 542. 11 240—NH(CH₂)₂OH Cl 3-Me-1-pra 558. 11 241 1-pyrr Cl 3-Me-1-pra 568. 11 2421-pipe Cl 3-Me-1-pra 582. 11 243 2-HOCH₂-1-pipe Cl 3-Me-1-pra 612. 11244 3-HOCH₂-1-pipe Cl 3-Me-1-pra 612. 11

NMR data of the compounds of some Examples are shown in Table 17. Theterm ‘NMR’ indicates δ(ppm) of the peaks in ¹H-NMR employing DMSO-d₆ asa measuring solvent unless otherwise indicated, using (CH₃)₄Si As aninternal standard. TABLE 17 Ex NMR 58 1.22-1.78(3H, m), 1.86-2.01(1H,m), 2.22(3H, s), 2.26-2.42(2H, m), 2.64-2.74(2H, m), 3.02-3.28(2H, m),3.88(1H, d, J=12.2Hz), 4.42(1H, d, J=12.2Hz), 4.70-4.93(1H, br),6.32(1H, d, J=2.4Hz), 6.65(1H, s), 6.85-6.98(1H, m), 7.00-7.12(2H, m),7.18(1H, t, J=7.8Hz), 7.22-7.29(1H, m), 7.35-7.50(2H, m), 7.54-7.62(1H,m), 7.81(1H, s), 8.37(1H, s). 62 1.12-1.32(4H, m), 1.56-1.72(2H, m),1.83-1.96(2H, m), 2.22(3H, s), 2.36-2.45(1H, br), 2.54-2.79(1H, br),3.04-3.23(1H, br), 3.29-3.38(1H, m), 3.44-3.57(1H, br), 4.52(1H, d,J=4.9Hz), 4.68-4.94(1H, br), 6.33(1H, d, J=2.5Hz), 6.36(1H, s),6.93-7.09(2H, m), 7.16(1H, dt, J=1.2, 7.8Hz), 7.25(1H, t, J=7.8Hz),7.33(1H, d, J=7.8Hz), 7.57(1H, d, J=7.8Hz), 7.84(1H, s), 8.09-8.18(1H,br), 8.38(1H, d, J=2.4Hz). 67 2.22(3H, s), 2.55-2.90(1H, br), 2.60(3H,s), 3.10-3.35(1H, br), 3.50-3.65(1H, br), 4.80-4.95(1H, br), 6.34(1H, d,J=2.4Hz), 6.65(1H, s), 7.00-7.96(10H, m), 8.20(1H, s), 8.38(1H, d,J=2.6Hz), 10.57(1H, s). 71 2.22(3H, s), 2.41-2.47(1H, br), 2.60-2.78(1H,br), 3.12-3.28(1H, br), 4.69-4.98(1H, br), 6.63(1H, d, J=2.4Hz),6.63(1H, s), 7.02(1H, d, J=7.8Hz), 7.05-7.14(1H, br), 7.20(1H, dt,J=1.5, 7.8Hz), 7.28(1H, t, J=7.8Hz), 7.34-7.41(2H, m), 7.44(1H, t,J=7.8Hz), 7.61(2H, t, J=7.8Hz), 7.83-7.88(2H, m), 7.95(1H, s), 8.07(1H,s), 8.37(1H, d, J=2.4Hz), 10.47(1H, s). 72 2.22(3H, s), 2.28-2.39(1H,br), 2.58-2.79(1H, br), 3.22-3.40(1H, br), 4.50-4.83(1H, br), 6.33(1H,d, J=2.4Hz), 6.65(1H, s), 7.03(1H, d, J=7.8Hz), 7.06-7.13(1H, br),7.21(1H, dt, J=1.5, 7.8Hz), 7.24-7.33(2H, m), 7.37(1H, d, J=7.8Hz),7.59(1H, d, J=8.3Hz), 7.71(2H, d, J=8.8Hz), 7.83-7.91(4H, m), 8.33(1H,d, J=2.4Hz), 10.56(1H, s). 73 2.23(3H, s), 2.34-2.47(1H, br),2.54-2.69(1H, br), 2.79(3H, d, J=4.4Hz), 3.00-3.28(1H, br),4.71-4.90(1H, br), 6.34(1H, d, J=2.4Hz), 6.63(1H, s), 6.96-7.14(2H, m),7.21(1H, t, J=7.8Hz), 7.29(1H, t, J=7.8Hz), 7.37(1H, d, J=7.8Hz),7.45(1H, t, J=7.8Hz), 7.52-7.64(2H, m), 8.07(1H, s), 8.38(1H, d,J=2.4Hz), 8.41-8.49(1H, m), 10.50(1H, s). 74 2.22(3H, s), 2.31(3H, s),2.55-2.90(1H, br), 3.10-3.35(1H, br), 3.50-3.65(1H, br), 4.80-4.95(1H,br), 6.33(1H, d, J=2.4Hz), 6.60(1H, s), 6.90-7.61(10H, m), 7.84(1H, s),8.38(1H, d, J=2.4Hz), 10.27(1H, s). 76 2.22(3H, s), 2.60-2.90(1H, br),3.05-3.35(1H, br), 3.50-3.65(1H, br), 4.51(2H, d, J=5.1Hz),4.76-4.90(1H, br), 5.23(1H, t, J=5.6Hz), 6.33(1H, d, J=2.4Hz), 6.61(1H,s), 6.98-7.39(7H, m), 7.51-7.63(3H, m), 7.84(1H, s), 8.38(1H, d,J=2.4Hz), 10.33(1H, s). 77 2.22(3H, s), 2.60-2.95(1H, br), 3.00-3.30(1H,br), 3.50-3.65(1H, br), 4.47(2H, d, J=5.5Hz), 4.75- 4.95(1H, br),5.13(1H, t, J=5.6Hz), 6.33(1H, d, J=2.4Hz), 6.61(1H, s), 6.99-7.39(7H,m), 7.56-7.61(3H, m), 7.84(1H, s), 8.37(1H, d, J=2.4Hz), 10.32(1H, s).78 2.22(3H, s), 2.72(2H, t, J=7.0Hz), 2.55-2.90(1H, br), 3.10-3.35(1H,br), 3.50-3.65(1H, br), 3.58-3.66(2H, m), 4.66(1H, t, J=5.2Hz),4.80-4.95(1H, br), 6.33(1H, d, J=2.4Hz), 6.60(1H, s), 6.95-7.61(10H, m),7.84(1H, s), 8.38(1H, d, J=2.4Hz), 10.29(1H, s). 79 1.33(3H, d,J=6.4Hz), 2.22(3H, s), 2.55-2.90(1H, br), 3.05-3.30(1H, br),3.50-3.65(1H, br), 4.67-4.76(1H, m), 4.75-4.90(1H, br), 5.20(1H, d,J=4.0Hz), 6.33(1H, d, J=2.4Hz), 6.60(1H, s), 7.00-7.39(7H, m),7.52-7.61(3H, m), 7.84(1H, s), 8.38(1H, d, J=2.4Hz), 10.33(1H, s). 812.22(3H, s), 2.45-2.55(1H, br), 2.70-2.80(1H, br), 3.15-3.25(1H, br),3.42(2H, t, J=6.1Hz), 4.51(1 H, q, J=5.4Hz), 4.69(1H, t, J=5.9Hz),4.75-4.95(1H, br), 5.18(1H, d, J=3.9Hz), 6.34(1H, d, J=2.4Hz), 6.61(1H,s), 7.01(1H, d, J=7.8Hz), 7.03-7.15(1H, br), 7.20(1H, dt, J=1.5, 7.8Hz),7.25-7.35(3 H, m), 7.38(1H, dd, J=7.8, 1.5Hz), 7.55-7.61(3H, m),7.85(1H, s), 8.38(1H, d, J=2.4Hz), 10.3(1H, s). 82 2.22(3H, s),2.55-2.90(1H, br), 3.10-3.35(1H, br), 3.32(3H, s), 3.50-3.65(1H, br),4.42(2H, s), 4.80-4.95(1H, br), 6.34(1H, d, J=2.4Hz), 6.61(1H, s),7.00-7.39(7H, m), 7.55-7.64(3H, m), 7.85(1H, s), 8.38(1H, d, J=2.4Hz),10.37(1H, s). 83 2.22(3H, s), 2.42-2.48(1H, br), 2.66-2.93(1H, br),3.09-3.27(1H, br), 3.38(2H, s), 4.69-5.00(1H, br), 6.33(1H, d, J=2.4Hz),6.51(1H, s), 6.91(1H, s), 7.02(2H, d, J=7.8Hz), 7.04-7.15(1H, br),7.20(1 H, t, J=7.8Hz), 7.24-7.33(2H, m), 7.37(1H, d, J=7.8Hz),7.46-7.63(4H, m), 7.84(1H, s), 8.38(1H, d, J=2.4Hz), 10.35(1H, s). 842.22(3H, s), 2.37(2H, t, J=7.8Hz), 2.43-2.48(1H, br), 2.63-2.74(1H, br),2.80(2H, t, J=7.8Hz), 3.19-3.24(1H, br), 4.75-4.94(1H, br), 6.34(1H, d,J=2.4Hz), 6.60(1H, s), 6.77(1H, s), 6.97(1H, d, J=7. 8Hz), 7.03(1H, d,J=7.8Hz), 7.06-7.14(1H, br), 7.17-7.34(5H, m), 7.37(1H, dd, J=1.0,7.8Hz), 7.44-7.52(1H, m), 7.59(1H, d, J=7.8Hz), 7.84(1H, d), 8.37(1H, d,J=2.4Hz), 10.31(1H, s). 85 2.22(3H, s), 2.42-2.48(1H, br), 2.69-2.82(1H,br), 3.22-3.29(1H, br), 4.74-5.02(1H, br), 6.34(1H, d, J=2.4Hz),6.62-6.67(2H, m), 7.03(1H, d, J=7.8Hz), 7.05-7.16(2H, m), 7.22(1H, dt,J=1.4, 7.8Hz), 7.27-7.33(2H, m), 7.36-7.44(3H, m), 7.51-7.65(3H, m),7.84(1H, s), 7.99(1H, s), 8.38(1H, d, J=2.4Hz), 10.43(1H, s). 862.22(3H, s), 2.55-2.90(1H, br), 3.10-3.35(1H, br), 3.50-3.65(1H, br),4.80-4.95(1H, br), 6.33(1H, d, J=2.4Hz), 6.64(1H, s), 6.91-7.66(10H, m),7.84(1H, s), 8.38(1H, d, J=2.4Hz), 10.57(1H, s). 87 2.22(3H, s),2.55-2.90(1H, br), 3.10-3.35(1H, br), 3.24(3H, s), 3.50-3.65(1H, br),4.80-4.95(1H, br), 6.34(1H, d, J=2.4Hz), 6.66(1H, s), 7.00-7.40(5H, m),7.57-7.69(3H, m), 7.84(1H, s), 7.95-8.00(1H, m), 8.26(1H, s), 8.38(1H,d, J=2.4Hz), 10.75(1H, s). 88 2.05(3H, s), 2.22(3H, s), 2.32-2.47(1H,br), 2.55-2.78(1H, br), 2.99-3.28(1H, br), 4.70-4.98(1H, br), 6.33(1H,d, J=2.4Hz), 6.60(1H, s), 7.02(1H, d, J=7.8Hz), 7.04-7.15(1H, br),7.17-7.39(6H, m), 7.60(1H, d, J=8.3Hz), 7.84(1H, s), 7.98(1H, s),8.38(1H, d, J=2.4Hz), 9.99(1H, s), 10.37(1H, s). 90 1.77-1.91(1H, m),2.22(3H, s), 2.32-2.47(2H, m), 2.69-2.83(1H, br), 3.19-3.27(3H, m),4.32-4.50(1H, m), 4.75-4.92(1H, br), 6.33(1H, d, J=2.4Hz), 6.42(1H, s),6.91-7.07(2H, m), 7.17(1H, dt, J=1.5, 7.8Hz), 7.24(1H, t, J=7.8Hz),7.32(1H, dd, J=1.5, 7.8Hz), 7.59(1H, d, J=8.3Hz), 7.84(1H, s), 7.91(1H,s), 8.37(1H, d, J=2.4Hz), 8.65-8.76(1H, m). 91 2.22(3H, s),2.32-2.47(1H, br), 2.62-2.90(1H, br), 3.09-3.23(1H, br), 3.25-3.31(2H,m), 4.22-4.30(1H, br), 4.37-4.44(1H, m), 4.61-5.00(2H, m), 6.33(1H, d,J=2.4Hz), 6.45(1H, s), 6.93-7.07(2H, m), 7.18(1H, dt, J=1.4, 7.8Hz),7.25(1H, t, J=7.8Hz), 7.31(1H, d, J=7.8Hz), 7.58(1H, d, J=7.8Hz),7.83(1H, s), 8.37(1H, d, J=2.4Hz), 8.74-8.98(1H, br). 92 1.04-1.12(1H,m), 2.07-2.19(2H, m), 2.22(3H, s), 2.34-2.45(1H, br), 2.57-2.93(1H, br),3.02-3.27(1H, br), 3.33-3.51(1H, m), 4.62-4.97(2H, br), 6.33(1H, d,J=2.4Hz), 6.45(1H, s), 6.90-7.08(2H, m), 7.16(1H, t, J=7.3Hz), 7.24(1H,t, J=7.3Hz), 7.31(1H, d, J=7.3Hz), 7.59(1H, d, J=7.3Hz), 7.84(1H, s),8.38(1H, s), 8.71-8.83(1H, br). 105 2.22(3H, s), 2.55-2.90(1H, br),3.05-3.30(1H, br), 3.50-3.65(1H, br), 4.45(2H, d, J=5.9Hz),4.75-4.90(1H, br), 6.33(1H, d, J=2.4Hz), 6.47(1H, s), 6.95-7.58(9H, m),7.82-7.95(4H, m), 8.37(1H, d, J=2.6Hz), 8.94(1H, s). 109 2.22(3H, s),2.41-2.47(1H, br), 2.55-2.64(1H, br), 3.09-3.26(1H, br), 4.46(2H, d,J=4.9Hz), 4.74-4.90(1H, br), 6.33(1H, d, J=2.4Hz), 6.49(1H, s),6.95-7.10(2H, m), 7.17(1H, dt, J=1.5, 7.8Hz), 7.25(1H, dt, J=1.5,7.8Hz), 7.29-7.36(3H, m), 7.48-7.60(3H., m), 7.77-7.84(3H, m), 8.37(1H,d, J=2.4Hz), 9.00(1H, s). 110 2.22(3H, s), 2.40-2.50(1H, br),2.67-2.89(1H, br), 3.11-3.23(1H, br), 4.73(2H, d, J=5.4Hz),4.76-4.90(1H, br), 6.34(1H, d, J=2.5Hz), 6.41(1H, s), 6.99(1H, d,J=7.8Hz), 7.19(1H, t, J=7.8Hz), 7.26(1H, t, J=7.8Hz), 7.33(1H, d,J=6.8Hz), 7.61(1H, d, J=8.3Hz), 7.79-7.88(3H, m), 8.35-8.45(2H, m),8.79(1H, d, J=4.8Hz), 9.30(1H, s). 119 2.22(3H, s), 2.35-2.55(1H, br),2.70(3H, s), 2.70-2.85(1H, br), 3.12-3.30(1H, br), 4.67(2H, brs),4.75-4.90(1H, br), 6.34(1H, d, J=2.5Hz), 6.53(1H, s), 6.99(1H, d,J=7.8Hz), 7.00-7.12(1H, br), 7.19(1H, td, J=7.8, 1.5Hz), 7.26(1H, d,J=7.8Hz), 7.33(1H, d, J=7.8Hz), 7.55-7.70(3H, m), 7.84(1H, s),8.23-8.33(1H, br), 8.39(1H, d, J=2.5Hz), 9.23(1H, brs). 144 1.27(6H, s),2.22(3H, s), 2.34-2.55(1H, br), 2.55-2.80(1H, br), 3.21-3.28(1H, br),3.45(2H, s), 4.70-4.96(1H, br), 4.86(1H, t, J=5.9Hz), 6.32(1H, s),6.33(1H, d, J=2.5Hz), 6.87-7.07(1H, br), 6.96(1 H, d, J=7.8Hz), 7.15(1H,t, J=7.3Hz), 7.22(1H, t, J=7.3Hz), 7.33(1H, d, J=7.3Hz), 7.56(1H, d,J=8.8Hz), 7.74(1H, s), 7.83(1H, s), 8.37(1H, d, J=3.5Hz). 162 2.24(3H,s), 2.34-2.45(1H, br), 2.57-2.70(1H, br), 3.06-3.20(1H, br),4.69-4.99(1H, br), 6.36(1 H, d, J=2.5Hz), 6.46(1H, s), 6.76(1H, d,J=7.8Hz), 7.02(1H, d, J=8.3Hz), 7.16(1H, dt, J=1.5, 7.8Hz), 7.24(1H, dt,J=1.5, 7.8Hz), 7.32(1H, dd, J=1.5, 7.8Hz), 7.36(1H, s), 7.85(1H, dd,J=1.5, 8.3Hz), 7.91(1H, s), 8.09(1H, d, J=1.5Hz), 8.46(1H, d, J=2.5Hz).163 2.22(3H, s), 2.37-2.45(1H, br), 2.71-2.87(1H, br), 3.08-3.29(3H, m),3.49(2H, t, J=6.4Hz), 4.70-4.92(1H, br), 6.36(1H, d, J=2.5Hz), 6.48(1H,s), 6.97(1H, d, J=7.8Hz), 7.03(1H, d, J=8.8Hz), 7.15(1H, dt, J=1.5,7.8Hz), 7.25(1H, dt, J=1.5, 7.8Hz), 7.34(1H, dd, J=1.8, 7.8Hz), 7.84(1H,dd, J=1.5, 8.8Hz), 8.09(1H, d, J=1.5Hz), 8.47(1H, d, J=2.5Hz), 8.51(1H,t, J=5.3Hz). 167 2.22(3H, s), 2.41(3H, s), 2.43-2.46(1H, br),2.57-2.64(1H, br), 3.00-3.21(1H, br), 4.71-4.99(1H, br), 6.24-6.31(1H,br), 6.37(1H, s), 6.57-6.87(2H, m), 7.09(1H, t, J=7.8Hz), 7.15(1H, t,J=7.8Hz), 7.25-7.39(3H, m), 7.58(1H, s), 7.84(1H, s), 8.27(1H, s). 1691.04(6H, s), 1.70(2H, t, J=6.3Hz), 2.43-2.48(1H, br), 2.53-2.57(1H, br),2.86-2.96(2H, br), 3.17-3.26(3H, m), 4.62-5.02(1H, br), 6.12-6.19(1H,m), 6.25(1H, s), 6.36-6.40(1H, br), 6.64-6.72(1H, br), 6.86-6.92(1H,br), 7.13-7.35(4H, m), 7.79(1H, s). 171 1.94-2.09(1H, m), 2.26-2.45(2H,m), 2.53-2.73(1H, br), 3.04-3.19(3H, m), 3.28-3.51(2H, m), 3.57-3.68(1H,m), 4.57-5.04(1H, br), 6.21-6.30(2H, br), 6.47(1H, s), 6.65-6.75(1H, m),6.84-6.91(1 H, m), 7.12-7.37(9H, m), 7.76-7.83(1H, br). 172 0.86(3H, t,J=7.3Hz), 0.97(3H, s), 1.33-1.44(2H, m), 1.60-1.77(2H, m), 2.33-2.47(1H,br), 2.54-2.71(1H, br), 2.85-2.98(2H, m), 3.16-3.26(3H, m),4.72-5.03(1H, br), 6.13-6.20(1H, m), 6.25(1 H, s), 6.33-6.42(1H, br),6.60-6.72(1H, br), 6.81-6.92(1H, br), 7.12-7.29(3H, m), 7.33(1H, s),7.75-7.84(1H, br). 176 1.03(3H, d, J=6.3Hz), 1.48-1.60(1H, m),1.99-2.10(1H, m), 2.24-2.47(2H, m), 2.54-2.80(2H, m), 3.10-3.38(4H, m),4.72-4.93(1H, br), 6.35(1H, s), 6.38-6.43(1H, m), 6.61(1H, s),6.64-6.75(2H, m), 7.14(1H, t, J=7.8Hz), 7.23(1H, t, J=7.8Hz), 7.29(1H,d, J=7.8Hz), 7.35(1H, s), 7.85(1H, s). 180 2.06(3H, s), 2.32-2.44(1H,br), 2.61-2.79(1H, br), 2.98-3.20(1H, br), 4.78-4.99(1H, br), 6.45(1H,s), 6.70(1H, d, J=7.8Hz), 7.03(1H, d, J=8.3Hz), 7.16(1H, dt, J=1.5,7.8Hz), 7.25(1H, dt, J=1.5, 7.8Hz), 7.32(1H, dd, J=1.5, 7.8Hz), 7.37(1H,s), 7.60(1H, s), 7.84(1H, dd, J=1.5, 8.3Hz), 7.92(1H, s), 8.09(1H, d,J=1.5Hz), 8.36(1H, s). 188 1.07(6H, s), 1.71(2H, t, J=6.4Hz),2.36-2.47(1H, br), 2.55-2.68(1H, br), 2.88-2.96(2H, br), 3.02-3.16(1H,br), 3.17-3.28(2H, br), 4.63-4.82(3H, m), 6.13-6.25(1H, m),6.33-6.42(1H, br), 6.47(1 H, s), 6.67-6.77(1H, m), 6.83-6.94(1H, m),7.13-7.38(3H, m), 7.79-7.80(2H, m), 8.41(1H, t, J=7.8Hz), 8.79(1H, d,J=4.9Hz), 9.20-9.29(1H, m). 213 1.04(6H, s), 1.69(2H, t, J=6.8Hz),2.42-2.48(1H, br), 2.53-2.70(1H, br), 2.87-2.95(2H, br), 3.18-3.25(5H,m), 3.43-3.50(2H, m), 4.71(1H, t, J=5.4Hz), 4.73-4.86(1H, br),6.10-6.19(1H, m), 6.27(1H, s), 6.34-6.40(1H, br), 6.61-6.71(1H, br),6.80-6.92(1H, br), 7.12-7.32(3H, m), 8.31-8.40(1 H, br). 215 1.03(3H, d,J=6.8Hz), 1.47-1.60(1H, m), 2.00-2.10(1H, m), 2.25-2.47(2H, m),2.57-2.82(2H, m), 3.14-3.50(8H, m), 4.73(1H, t, J=5.4Hz), 4.76-4.92(1H,br), 6.34-6.44(2H, m), 6.62(1H, s), 6.66-6.72(2H, m), 7.16(1H, t,J=7.8Hz), 7.22(1H, t, J=7.8Hz), 7.32(1H, d, J=7.8Hz), 8.43(1H, s). 2161.03(3H, d, J=6.8Hz), 1.50-1.60(1H, m), 2.00-2.05(1H, m), 2.25-2.40(2H,m), 2.41-2.55(1H, m), 2.70-2.80(1H, m), 3.20-3.40(7H, m), 3.47(2H, q,J=5.9Hz), 4.75-4.90(1H, br), 6.37(1H, s), 6.37-6.42(1H, m), 6.62(1H, s),6.63-6.75(2H, m), 7.16(1H, t, J=7.3Hz), 7.23(1H, t, J=7.3Hz), 7.32(1H,d, J=7.3Hz), 8.42(1H, s). 220 1.81-1.96(4H, m), 2.32-2.41(1H, br),2.54-2.67(1H, br), 3.06-3.17(4H, m), 3.27-3.49(1H, br), 3.78(2H, s),4.62-5.01(1H, br), 6.13-6.22(1H, m), 6.34(1H, s), 6.37-6.45(1H, m),6.62-6.73(1H, m), 6.82-6.91(1H, m), 7.10-7.35(5H, m), 5.50-8.64(11H,br). 221 1.02(3H, d, J=5.9Hz), 1.45-1.55(1H, m), 1.95-2.10(1H, m),2.25-2.50(3H, m), 2.65-2.75(2H, m), 3.00-3.35(3H, m), 3.70-3.80(2H, m),4.70-4.95(1H, m), 6.15-6.20(1H, m), 6.34(1H, s), 6.39(1H, s),6.60-6.70(1H, br), 6.80-6.90(1H, br), 7.10-7.40(5H, m), 8.50-8.60(1H,br). 222 1.02(3H, d, J=5.9Hz), 1.45-1.55(1H, m), 1.97-2.08(1H, m),2.25-2.60(3H, m), 2.65-2.75(2H, m), 3.05-3.35(3H, m), 3.70-3.80(2H, m),4.65-4.80(1H, m), 6.10-6.20(1H, m), 6.34(1H, s), 6.39(1H, s),6.60-6.70(1H, br), 6.80-6.90(1H, br), 7.10-7.40(5H, m), 8.50-8.60(1H,br). 223 1.04(6H, s), 1.69(2H, t, J=6.4Hz), 2.44-2.47(1H, br),2.53-2.69(1H, br), 2.87-2.95(2H, br), 3.17-3.27(3H, m), 3.71-3.77(2H,m), 4.77-4.98(1H, br), 6.11-6.19(1H, m), 6.34(1H, s), 6.35-6.41(1H, br),6.62-6.73(1H, br), 6.83-6.92(1H, br), 7.10-7.36(5H, m), 8.58(1H, s). 2241.95-2.09(1H, m), 2.27-2.36(1H, m), 2.42-2.48(1H, br), 2.52-2.58(1H,br), 3.11-3.20(1H, m), 3.23-3.33(2H, m), 3.35-3.51(2H, m), 3.58-3.66(1H,m), 3.74(2H, d, J=3.9Hz), 4.48-5.11(1H, br), 6.21-6.26(1H, m), 6.34(1H,s), 6.44-6.52(1H, br), 6.65-6.76(1H, br), 6.83-6.92(1H, m), 7.12(1H, s),7.16-7.34(9H, m), 8.54-8.63(1H, br). 225 0.86(3H, t, J=7.3Hz), 0.97(3H,s), 1.34-1.44(2H, m), 1.61-1.76(2H, m), 2.42-2.48(1H, br), 2.52-2.57(1H,br), 2.85-2.97(2H, m), 3.15-3.27(3H, m), 3.74(2H, d, J=4.4Hz),4.70-5.03(1H, br), 6.11-6.20(1H, m), 6.34(1H, s), 6.36-6.45(1H, br),6.62-6.74(1H, br), 6.82-6.95(1H, m), 7.10-7.34(5H, m), 8.53-8.64(1H,br). 227 1.03(3H, d, J=5.8Hz), 1.48-1.60(1H, m), 1.99-2.10(1H, m),2.24-2.36(2H, m), 2.70-2.81(1H, m), 3.00-3.42(5H, m), 3.69-3.80(2H, br),4.78-4.82(1H, br), 6.39(1H, d, J=7.8Hz), 6.43(1H, s), 6.62(1H, s),6.65-6.74(2H, m), 7.10-7.29(4H, m), 7.35(1H, d, J=8.4Hz), 8.65(1H, s).228 1.03(3H, d, J=6.3Hz), 1.50-1.60(1H, m), 1.95-2.10(1H, m),2.20-2.40(2H, m), 2.70-2.80(1H, m), 3.00-3.40(5H, m), 3.70-3.80(2H, br),4.70-4.95(1H, br), 6.39(1H, d, J=7.8Hz), 6.43(1H, s), 6.62(1H, s),6.65-6.75(2H, m), 7.10-7.30(4H, m), 7.35(1H, d, J=8.4Hz), 8.64(1H, s).230 0.90(6H, d, J=5.9Hz), 2.23-2.50(4H, m), 2.55-2.75(1H, br),2.80-3.00(2H, br), 3.01-3.20(1H, br), 3.25-3.40(1H, m), 3.70-3.80(2H,br), 4.75-4.90(1H, br), 6.30-6.40(1H, m), 6.43(1H, s), 6.60(1 H, s),6.68(1H, d, J=8.3Hz), 6.72(1H, d, J=6.8Hz), 7.10-7.30(4H, m), 7.35(1H,d, J=7.4Hz), 8.63(1 H, s). 238 2.23(3H, s), 2.33-2.46(1H, br),2.54-2.79(1H, br), 2.98-3.27(1H, br), 4.62-4.97(1H, br), 6.24(1H, s),6.37(1H, d, J=2.4Hz), 7.07-7.54(6H, m), 7.75-7.92(2H, m), 8.05(1H, s).243 1.20-1.85(6H, m), 2.22(3H, s), 2.25-2.90(5H, m), 3.00-4.35(5H, m),4.45-4.70(1H, m), 4.75-4.90(1H, br), 6.33(1H, d, J=2.5Hz), 6.39(1H, s),6.98(1H, d, J=7.8Hz), 7.00-7.12(1H, br), 7. 16(1H, t, J=7.1Hz), 7.25(1H,t, J=7.3Hz), 7.37(1H, d, J=7.4Hz), 7.57(1H, d, J=7.8Hz), 7.83(1H, s),8.38(1H, d, J=2.4Hz), 8.40-8.55(1H, m). 244 1.20-1.75(6H, m), 2.22(3H,s), 2.30-2.50(2H, m), 2.65-3.01(3H, m), 3.20-3.40(3H, m), 3.70-3.80(1H,m), 4.07(1H, s), 4.54(0.5H, t, J=5.4Hz), 4.63(0.5H, t, J=5.4Hz),4.65-4.80(1H, br), 6.33(1H, d, J=2.5Hz), 6.40(1H, s), 6.98(1H, d,J=7.8Hz), 7.00-7.10(1H, br), 7.17(1H, dt, J=1.5, 7.8Hz), 7.25(1H, dt,J=1.0, 7.8Hz), 7.37(1H, d, J=7.3Hz), 7.57(1H, d, J=7.8Hz), 7.83(1H, s),8.38(1H, d, J=2.5Hz), 8.47-8.60(1H, br).

The structures of the compounds of the present invention are shown inTable 18. These compounds can be easily synthesized by methods that areself-evident to an ordinarily skilled person, or with modified methods.The ‘No’ in the Table indicates compound number. TABLE 18

No R¹ R² R³ R⁴ R⁵ A1 —NH-(4-HO₂C—Ph) Cl 3-Me-pra H H A2 —NH-(2-HO₂C—Ph)Cl 3-Me-pra H H A3 —NH-(4-Me₂N—Ph) Cl 3-Me-pra H H A4 —NH-(4-cyano-Ph)Cl 3-Me-pra H H A5 —NH-(3-F₃C—Ph) Cl 3-Me-pra H H A6 —NH-(2-MeO—Ph) Cl3-Me-pra H H A7 —NH-(2-F—Ph) Cl 3-Me-pra H H A8 —NHCH2-(2-H₂NOC—Ph) Cl3-Me-pra H H A9 —NH-(6-HO-3-py) Cl 3-Me-pra H H A10—NH-(6-Cl-pyridazin-3-yl) Cl 3-Me-pra H H A11 —NH-(6-Me-2-py) Cl3-Me-pra H H A12 —NH-(5-H₂NOC-2-py) Cl 3-Me-pra H H A13 —NH-(2-thia) Cl3-Me-pra H H A14 —NH-(1-Me-2-imid) Cl 3-Me-pra H H A15—NH-(pyrazin-2-yl) Cl 3-Me-pra H H A16 —N(Me)-(6-HO-3-py) Cl 3-Me-pra HH A17 —NHCH₂-(4-H₂NOC-2-py) Cl 3-Me-pra H H A18 —N(Me)CH₂-(3-py) Cl3-Me-pra H H A19 —NHCH₂-(4-F-2-py) Cl 3-Me-pra H H A20—NHCH₂-(pyrimidin-2-yl) Cl 3-Me-pra H H A21 2-H₂NOC-pyrr Cl 3-Me-pra H HA22 2-H₂NOC-pipe Cl 3-Me-pra H H A23

Cl 3-Me-pra- H H A24

Cl 3-Me-pra- H H A25

Cl 3-Me-pra- H H A26

Cl 3-Me-pra- H H A27

Cl 3-Me-pra- H H A28

Cl 3-Me-pra- H H A29

Cl 3-Me-pra- H H A30

Cl 3-Me-pra- H H A31

Cl 3-Me-pra- H H A32

Cl 3-Me-pra- H H A33

Cl 3-Me-pra- H H A34

Cl 3-Me-pra- H H A35

Cl 3-Me-pra- H H A36

Cl 3-Me-pra- H H A37

Cl 3-Me-pra- H H A38

Cl 3-Me-pra- H H A39

Cl 3-Me-pra- H H A40

Cl 3-Me-pra- H H A41

Cl 3-Me-pra- H H A42

Cl 3-Me-pra- H H A43

Cl 3-Me-pra- H H A44 —NHCH₂-(2-py) Br 3-Me-pra- H H A45 —NH(CH₂)₂OH Br3-Me-pra- H H A46 —NHCH₂CONH₂ Br 3-Me-pra- H H A47 —NH₂ Br 3-Me-pra- H HA48 —NHCH₂-(2-py) Me 3-Me-pra- H H A49 —NH(CH₂)₂OH Me 3-Me-pra- H H A50—NHCH₂CONH₂ Me 3-Me-pra- H H A51 —NH₂ Me 3-Me-pra- H H A52 —NH(CH₂)₂OHMe pyrr- H H A53 —NHCH₂-(6-HO-2-py) Me pyrr- H H A54 —NHCH₂-(2-py) Mepyrr- H H A55 —N((CH₂)₂OH)₂ Me pyrr- H H A56 —NH₂ Me pyrr- H H A57—NHCH₂CONH₂ Me 3-Me-pyrr- H H A58 —NHCH₂-(2-py) Me 3-Me-pyrr- H H A59—NH₂ Me 3-Me-pyrr- H H A60 —NH(CH₂)₂OH Me 3-Me-pyrr- H H A61 —NHCH₂CONH₂Me 3,3-diF-pyrr- H H A62 —NHCH₂CONH₂ Me 3,4-diMe-pyrr- H H A63 —NH₂ Me3,3-diF-pyrr- H H A64 —NH₂ Me 3,4-diMe-pyrr- H H A65 —NHCH₂-(6-HO-2-py)CF₃ 3-Me-pra- H H A66 —NHCH₂-(6-Me-2-py) CF₃ 3-Me-pra- H H A67

CF₃ 3-Me-pra- H H A68 —NHCH₂-(6-HO-2-py) CF₃ 3-Me-pra- H H A69—N((CH₂)₂OH)₂ CF₃ 3-Me-pra- H H A70 —NHCH₂-(6-HO-2-py) CF₃ pyrr- H H A71—NHCH₂-(2-py) CF₃ pyrr- H H A72 —N((CH₂)₂OH)₂ CF₃ pyrr- H H A73—N((CH₂)₂OH)₂ Cl 3-Me-pyrr- H H A74 —NHCH₂-(2-py) Cl 2-H₂NOC-pyrr- H HA75 —NHCH₂-(2-py) Cl 3-HO-pipe- H H A76 —NHCH₂-(2-py) CF₃ 3-HO-pipe- H HA77 —NHCH₂-(2-py) Cl 3-MeO-pyrr- H H A78 —NHCH₂-(2-py) CF₃ 3-MeO-pyrr- HH A79 —NHCH₂-(2-py) Cl 4-NC-pipe- H H A80 —NHCH₂-(2-py) Cl3,4-diMe-pyrr- H H A81 —NH(CH₂)₂OH Cl 2,4-diMe-pyrr- H H A82—NHCH₂-(2-py) Cl

H H A83 —NH(CH₂)₂OH Cl

H H A84 —NHCH₂CONH₂ Cl

H H A85 —NH(CH₂)₂OH CF₃

H H A86 —NHCH₂-(2-py) CF₃

H H A87 —NHCH₂-(2-py) Cl 3-Me-pra- H 7-Me A88 —NHCH₂-(2-py) Cl3-Me-pyrr- H 7-Me A89 —NHCH₂-(2-py) Cl 3-Me-pra- H 7-Cl A90—NHCH₂-(2-py) Cl 3-Me-pyrr- H 7-Cl A91 —NHCH₂-(2-py) CF₃ 3-Me-pra H 7-MeA92 —NHCH₂-(2-py) CF₃ 3-Me-pyrr H 7-Me A93 —NHCH₂-(2-py) CF₃ 3-Me-pra H7-Cl A94 —NHCH₂-(2-py) CF₃ 3-Me-pyrr H 7-Cl A95 —NHCH₂-(2-py) Cl3-Me-pra H 8-Me A96 —NHCH₂-(2-py) Cl 3-Me-pyrr H 8-Me A97 —NHCH₂-(2-py)Cl 3-Me-pra H 8-Cl A98 —NHCH₂-(2-py) Cl 3-Me-pyrr H 8-Cl A99—NHCH₂-(2-py) CF₃ 3-Me-pra H 8-Me A100 —NHCH₂-(2-py) CF₃ 3-Me-pyrr H8-Me A101 —NHCH₂-(2-py) CF₃ 3-Me-pra H 8-Cl A102 —NHCH₂-(2-py) CF₃3-Me-pyrr H 8-Cl A103 —NHCH₂-(2-py) Cl H 3-Me-pra- H A104 —NHCH₂-(2-py)Cl H 3-Me-pyrr- H A105 —NHCH₂CONH₂ Cl H 3-Me-pyrr- H A106 —NHCH₂-(2-py)Cl H pyrr- H A107 —NHCH₂-(2-py) CF₃ H 3-Me-pra- H A108 —NHCH₂-(2-py) CF₃H 3-Me-pyrr- H A109 —NHCH₂CONH₂ CF₃ H 3-Me-pyrr- H A110 —NHCH₂-(2-py)CF₃ H pyrr- H A111 —NH(CH₂)₂OH Cl 3,3-diF-pyrr H H A112 —NHCH₂CONH₂ Cl3,3-diF-pyrr H H A113 —NH(CH₂)₂OH CF₃ 3,3-diF-pyrr H H A114 —NHCH₂CONH₂CF₃ 3,3-diF-pyrr H H A115 —NH(CH₂)₂OH Cl 3-CF₃-pyrr H H A116 —NHCH₂CONH₂Cl 3-CF₃-pyrr H H A117 —NH(CH₂)₂OH CF₃ 3-CF₃-pyrr H H A118 —NHCH₂CONH₂CF₃ 3-CF₃-pyrr H H A119 —NH(CH₂)₂OH Cl 2,5-dihydropyrrol-1-yl H H A120—NHCH₂CONH₂ Cl 2,5-dihydropyrrol-1-yl H H A121 —NH₂ Cl2,5-dihydropyrrol-1-yl H H A122 —NH(CH₂)₂OH Cl 3,4-diMe-1-pyrr H H A123—NHCH₂CONH₂ Cl 3,4-diMe-1-pyrr H H A124 —NH₂ Cl 3,4-diMe-1-pyrr H H A125—NHCH₂CONH₂ Cl

H H A126 —NH₂ Cl

H H A127 —NHCH₂CONH₂ Cl 3,4-diHO-1-pyrr H H A128 —NH₂ Cl 3,4-diHO-1-pyrrH H A129 —NH-(3-HOCH₂—(E)—CH═CH—Ph) CF₃ 3-Me-pra H H A130—NH-(3-HO₂C—(E)—CH═CH—Ph) CF₃ 3-Me-pra H H A131 —NH-(3-Ph—(E)—CH═CH—Ph)CF₃ 3-Me-pra H H A132 —NH-2-(5-H₂NOC—(E)—CH═CH—Py) CF₃ 3-Me-pra H H A133OMe CF₃ H₂N—(Ac)N— H H A134 OEt CF₃ H₂N—(Ac)N— H H A135 OEt CF₃H₂N—(Boc)N— H H A136 OiPr CF₃ H₂N—(Boc)N— H H A137 OEt Cl H₂N—(Boc)N— HH A138 OiPr Cl H₂N—(Boc)N— H H A139 OEt CF₃ H₂N—HN— H H A140 OiPr CF₃H₂N—HN— H H A141 OEt Cl H₂N—HN— H H A142 OiPr Cl H₂N—HN— H H A143—NHCH₂CONH₂ CF₃ 3-Me-pra Me H A144 —NH₂ CF₃ 3-Me-pra Me H A145—NHCH₂CONH₂ CF₃ 3-Me-pra F H A146 —NH₂ CF₃ 3-Me-pra F H A147 —NHCH₂CONH₂CF₃ 3-Me-pyrr F H A148 —NH₂ CF₃ 3-Me-pyrr F H A149 —NH₂ CF₃ 3-Me-pyrr MeH A150 —NH-(4-H₂NOC—Ph) CF₃ 3-Me-pra H H A151 —NH-(3-H₂NOC—Ph) CF₃3-Me-pra H H A152 —NH-(3-Me—Ph) CF₃ 3-Me-pra H H A153 —NH-(4-HOCH₂—Ph)CF₃ 3-Me-pra H H A154 —NH-(3-HOCH₂—Ph) CF₃ 3-Me-pra H H A155—NH-(4-MeOCH₂—Ph) CF₃ 3-Me-pra H H A156 —NHCH₂-(4-H₂NOC—Ph) CF₃ 3-Me-praH H A157 —NH-(3-Ms—Ph) CF₃ 3-Me-pra H H A158 —NH-(3-Ac—Ph) CF₃ 3-Me-praH H A159 —NHCH₂-(4-H₂NO₂S—Ph) CF₃ 3-Me-pra H H A160 —NH-(2-HO-cHex) CF₃3-Me-pra H H A161 —NH-(3-H₂NOCCH₂—Ph) CF₃ 3-Me-pra H H A162—NH-(3-H₂NOC(CH₂)₂—Ph) CF₃ 3-Me-pra H H A163 —NH-(3-H₂NOC—(E)—CH═CH—Ph)CF₃ 3-Me-pra H H A164 —NH-(3-AcNH—Ph) CF₃ 3-Me-pra H H A165—NH-(4-H₂NOC—Ph) CF₃ 3-Me-pyrr H H A166 —NH-(3-H₂NOC—Ph) CF₃ 3-Me-pyrr HH A167 —NH-(3-Me—Ph) CF₃ 3-Me-pyrr H H A168 —NH-(4-HOCH₂—Ph) CF₃3-Me-pyrr H H A169 —NH-(3-HOCH₂—Ph) CF₃ 3-Me-pyrr H H A170—NH-(4-MeOCH₂—Ph) CF₃ 3-Me-pyrr H H A171 —NH-(3-Ms—Ph) CF₃ 3-Me-pyrr H HA172 —NH-(3-Ac—Ph) CF₃ 3-Me-pyrr H H A173 —NHCH₂-(4-H₂NO₂S—Ph) CF₃3-Me-pyrr H H A174 —NH-(2-HO-cHex) CF₃ 3-Me-pyrr H H A175—NH-(3-H₂NOCCH₂—Ph) CF₃ 3-Me-pyrr H H A176 —NH-(3-H₂NOC(CH₂)₂—Ph) CF₃3-Me-pyrr H H A177 —NH-(3-H₂NOC—(E)—CH═CH—Ph) CF₃ 3-Me-pyrr H H A178—NH-(3-AcNH—Ph) CF₃ 3-Me-pyrr H H A179 —NH(4-H₂NOC—Ph) Cl 3-Me-pyrr H HA180 —NH-(3-H₂NOC—Ph) Cl 3-Me-pyrr H H A181 —NH-(3-Me—Ph) Cl 3-Me-pyrr HH A182 —NH-(4-HOCH₂—Ph) Cl 3-Me-pyrr H H A183 —NH-(3-HOCH₂—Ph) Cl3-Me-pyrr H H A184 —NH-(4-MeOCH₂—Ph) Cl 3-Me-pyrr H H A185 —NH-(3-Ms—Ph)Cl 3-Me-pyrr H H A186 —NH-(3-Ac—Ph) Cl 3-Me-pyrr H H A187—NHCH₂-(4-H₂NO₂S—Ph) Cl 3-Me-pyrr H H A188 —NH-(2-HO-cHex) Cl 3-Me-pyrrH H A189 —NH-(3-H₂NOCCH₂—Ph) Cl 3-Me-pyrr H H A190—NH-(3-H₂NOC(CH₂)₂—Ph) Cl 3-Me-pyrr H H A191 —NH-(3-H₂NOC—(E)—CH═CH—Ph)Cl 3-Me-pyrr H H A192 —NH-(3-AcNH—Ph) Cl 3-Me-pyrr H H

1. 4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivativerepresented by the general Formula (I) or a pharmaceutically acceptablesalt thereof:

wherein the symbols have the following meanings: R¹: —OH, —O-loweralkyl, or an optionally substituted amino; R²: lower alkyl which may besubstituted with one or more halogen, or halogen; R³ and R⁴: one is —H,lower alkyl, or halogen, and the other is an optionally substitutednonaromatic cyclic amino or an optionally substituted aromatic cyclicamino; and R⁵: —H, lower alkyl, or halogen.
 2. The compound according toclaim 1, wherein R¹ is —OH, —O-lower alkyl, a group represented by thefollowing general Formula (II), or a group represented by the followinggeneral Formula (III):

wherein the symbols have the following meanings: A: a single bond, loweralkylene, or -lower alkylene-C(═O)—; R¹¹: lower alkyl which may besubstituted with a group selected from the group consisting of —OH,—O-lower alkyl, —CO₂H, —CO₂-lower alkyl, and carbamoyl which may besubstituted with one or two lower alkyl, or —H; R¹²: (1) when A is asingle bond or lower alkylene, R¹² is aryl, cycloalkyl, aromaticheterocycle, or nonaromatic heterocycle, each of which may besubstituted, or —H, —OH, —O-lower alkyl, —CO₂H, —CO₂-lower alkyl, orcarbamoyl which may be substituted with one or two lower alkyls; and (2)when A is -lower alkylene-C(═O)—, R¹² is a group represented by theabove general Formula (III), or a group represented by the followinggeneral Formula (IV),

B: a single bond, or lower alkylene; and R¹³ and R¹⁴: optionallysubstituted nonaromatic cyclic amino, bonded together with an adjacentnitrogen atom.
 3. The compound according to claim 2, wherein R¹ is agroup represented by the general Formula (II), or a group represented bythe general Formula (III).
 4. The compound according to claim 3, whereinR³ is an optionally substituted nonaromatic cyclic amino, or anoptionally substituted aromatic cyclic amino; R⁴ is —H, lower alkyl, orhalogen; and R⁵ is —H.
 5. The compound according to claim 4, wherein R⁴is —H.
 6. The compound according to any one of claim 1 to claim 5,wherein the compound is selected from the group consisting of(2Z)-2-{1-[2-chloro-4-(3-methyl-1H-pyrazol-1-yl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}-N-(pyridin-2-ylmethyl)acetamide;(2Z)-N-(2-amino-2-oxoethyl)-2-[1-(2-chloro-4-pyrrolidin-1-ylbenzoyl)-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene] acetamide;(2Z)-2-{4,4-difluoro-1-[4-(3-methyl-1H-pyrazol-1-yl)-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetamide;(2Z)-N-(2-amino-2-oxoethyl)-2-{4,4-difluoro-1-[4-[(3R)-3-methylpyrrolidin-1-yl]-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetamide;(2Z)-2-{4,4-difluoro-1-[4-(3R)-3-methylpyrrolidin-1-yl]-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}-N-(2-hydroxehtyl)acetamide;(2Z)-N-(2-amino-2-oxoethyl)-2-{4,4-difluoro-1-[4-(3S)-3-methylpyrrolidin-1-yl]-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetamide;(2Z)-2-{4,4-difluoro-1-[4-[(3-methyl-1H-pyrazol-1-yl)-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene]-N-(2-hydroxyethyl)acetamide;(2Z)-N-(2-amino-2-oxoethyl)-2-(1-{2-chloro-4-[(3R)-3-methylpyrrolidin-1-yl]benzoyl}-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene)acetamide;(2Z)-N-(2-amino-2-oxoethyl)-2-(1-{2-chloro-4-[(3S)-3-methylpyrrolidin-1-y]benzoyl}-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene)acetamide;(2Z)-2-{4,4-difluoro-1-[4-(4-methyl-1H-pyrazol-1-yl)-2-(trifluoromethyl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetamide;(2Z)-N-(2-amino-2-oxoethyl)-2-{1-[4-(3,4-dimethylpyrrolidin-1yl)-2-(trifluoromethyl)benzoyl]-4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepin-5-ylidene}acetamide;(2Z)-2-{4,4-difluoro-1-[2-methyl-4-(3-metyl-1H-pyrazol-1-yl)benzoyl]-1,2,3,4-tetrahydro-5H-1-benzazepine-5-ylidene}acetamide;and a pharmaceutically acceptable salt thereof.
 7. A pharmaceuticalcomposition comprising the compound of claim 1 as an active ingredient.8. The pharmaceutical composition according to claim 7, wherein thepharmaceutical composition is a drug for the treatment of centraldiabetes insipidus or nocturia.
 9. The pharmaceutical compositionaccording to claim 7, wherein the pharmaceutical composition is anarginine vasopressin V₂ receptor agonist. 10.4,4-difluoro-1,2,3,4-tetrahydro-5H-1-benzazepine derivative representedby the general Formula (V) or a pharmaceutically acceptable saltthereof:

wherein the symbols have the following meanings: R²¹: lower alkyl; R²²:chloro or trifluoromethyl; and R²³ and R²⁴: one is —H, and the other isan optionally protected hydrazino group.